                         SEQUENCE LISTING

<110>  Cambridge Enterprise Limited
 
<120>  Combination Therapy

<130>  P/74711.WO01/MR

<150>  GB 1603653.5
<151>  2016-03-02

<160>  84    

<170>  PatentIn version 3.5

<210>  1
<211>  1275
<212>  DNA
<213>  Homo sapiens


<220>
<221>  CDS
<222>  (1)..(1275)

<400>  1
atg ggc tct ctg gtc ctg aca ctg tgc gct ctt ttc tgc ctg gca gct         48
Met Gly Ser Leu Val Leu Thr Leu Cys Ala Leu Phe Cys Leu Ala Ala           
1               5                   10                  15                

tac ttg gtt tct ggc agc ccc atc atg aac cta gag cag tct cct ctg         96
Tyr Leu Val Ser Gly Ser Pro Ile Met Asn Leu Glu Gln Ser Pro Leu           
            20                  25                  30                    

gaa gaa gat atg tcc ctc ttt ggt gat gtt ttc tca gag caa gac ggt        144
Glu Glu Asp Met Ser Leu Phe Gly Asp Val Phe Ser Glu Gln Asp Gly           
        35                  40                  45                        

gtc gac ttt aac aca ctg ctc cag agc atg aag gat gag ttt ctt aag        192
Val Asp Phe Asn Thr Leu Leu Gln Ser Met Lys Asp Glu Phe Leu Lys           
    50                  55                  60                            

aca cta aac ctc tct gac atc ccc acg cag gat tca gcc aag gtg gac        240
Thr Leu Asn Leu Ser Asp Ile Pro Thr Gln Asp Ser Ala Lys Val Asp           
65                  70                  75                  80            

cca cca gag tac atg ttg gaa ctc tac aac aaa ttt gca aca gat cgg        288
Pro Pro Glu Tyr Met Leu Glu Leu Tyr Asn Lys Phe Ala Thr Asp Arg           
                85                  90                  95                

acc tcc atg ccc tct gcc aac atc att agg agt ttc aag aat gaa gat        336
Thr Ser Met Pro Ser Ala Asn Ile Ile Arg Ser Phe Lys Asn Glu Asp           
            100                 105                 110                   

ctg ttt tcc cag ccg gtc agt ttt aat ggg ctc cga aaa tac ccc ctc        384
Leu Phe Ser Gln Pro Val Ser Phe Asn Gly Leu Arg Lys Tyr Pro Leu           
        115                 120                 125                       

ctc ttc aat gtg tcc att cct cac cat gaa gag gtc atc atg gct gaa        432
Leu Phe Asn Val Ser Ile Pro His His Glu Glu Val Ile Met Ala Glu           
    130                 135                 140                           

ctt agg cta tac aca ctg gtg caa agg gat cgt atg ata tac gat gga        480
Leu Arg Leu Tyr Thr Leu Val Gln Arg Asp Arg Met Ile Tyr Asp Gly           
145                 150                 155                 160           

gta gac cgg aaa att acc att ttt gaa gtg ctg gag agc aaa ggg gat        528
Val Asp Arg Lys Ile Thr Ile Phe Glu Val Leu Glu Ser Lys Gly Asp           
                165                 170                 175               

aat gag gga gaa aga aac atg ctg gtc ttg gtg tct ggg gag ata tat        576
Asn Glu Gly Glu Arg Asn Met Leu Val Leu Val Ser Gly Glu Ile Tyr           
            180                 185                 190                   

gga acc aac agt gag tgg gag act ttt gat gtc aca gat gcc atc aga        624
Gly Thr Asn Ser Glu Trp Glu Thr Phe Asp Val Thr Asp Ala Ile Arg           
        195                 200                 205                       

cgt tgg caa aag tca ggc tca tcc acc cac cag ctg gag gtc cac att        672
Arg Trp Gln Lys Ser Gly Ser Ser Thr His Gln Leu Glu Val His Ile           
    210                 215                 220                           

gag agc aaa cac gat gaa gct gag gat gcc agc agt gga cgg cta gaa        720
Glu Ser Lys His Asp Glu Ala Glu Asp Ala Ser Ser Gly Arg Leu Glu           
225                 230                 235                 240           

ata gat acc agt gcc cag aat aag cat aac cct ttg ctc atc gtg ttt        768
Ile Asp Thr Ser Ala Gln Asn Lys His Asn Pro Leu Leu Ile Val Phe           
                245                 250                 255               

tct gat gac caa agc agt gac aag gag agg aag gag gaa ctg aat gaa        816
Ser Asp Asp Gln Ser Ser Asp Lys Glu Arg Lys Glu Glu Leu Asn Glu           
            260                 265                 270                   

atg att tcc cat gag caa ctt cca gag ctg gac aac ttg ggc ctg gat        864
Met Ile Ser His Glu Gln Leu Pro Glu Leu Asp Asn Leu Gly Leu Asp           
        275                 280                 285                       

agc ttt tcc agt gga cct ggg gaa gag gct ttg ttg cag atg aga tca        912
Ser Phe Ser Ser Gly Pro Gly Glu Glu Ala Leu Leu Gln Met Arg Ser           
    290                 295                 300                           

aac atc atc tat gac tcc act gcc cga atc aga agg aac gcc aaa gga        960
Asn Ile Ile Tyr Asp Ser Thr Ala Arg Ile Arg Arg Asn Ala Lys Gly           
305                 310                 315                 320           

aac tac tgt aag agg acc ccg ctc tac atc gac ttc aag gag att ggg       1008
Asn Tyr Cys Lys Arg Thr Pro Leu Tyr Ile Asp Phe Lys Glu Ile Gly           
                325                 330                 335               

tgg gac tcc tgg atc atc gct ccg cct gga tac gaa gcc tat gaa tgc       1056
Trp Asp Ser Trp Ile Ile Ala Pro Pro Gly Tyr Glu Ala Tyr Glu Cys           
            340                 345                 350                   

cgt ggt gtt tgt aac tac ccc ctg gca gag cat ctc aca ccc aca aag       1104
Arg Gly Val Cys Asn Tyr Pro Leu Ala Glu His Leu Thr Pro Thr Lys           
        355                 360                 365                       

cat gca att atc cag gcc ttg gtc cac ctc aag aat tcc cag aaa gct       1152
His Ala Ile Ile Gln Ala Leu Val His Leu Lys Asn Ser Gln Lys Ala           
    370                 375                 380                           

tcc aaa gcc tgc tgt gtg ccc aca aag cta gag ccc atc tcc atc ctc       1200
Ser Lys Ala Cys Cys Val Pro Thr Lys Leu Glu Pro Ile Ser Ile Leu           
385                 390                 395                 400           

tat tta gac aaa ggc gtc gtc acc tac aag ttt aaa tac gaa ggc atg       1248
Tyr Leu Asp Lys Gly Val Val Thr Tyr Lys Phe Lys Tyr Glu Gly Met           
                405                 410                 415               

gcc gtc tcc gaa tgt ggc tgt aga tag                                   1275
Ala Val Ser Glu Cys Gly Cys Arg                                           
            420                                                           


<210>  2
<211>  424
<212>  PRT
<213>  Homo sapiens

<400>  2

Met Gly Ser Leu Val Leu Thr Leu Cys Ala Leu Phe Cys Leu Ala Ala 
1               5                   10                  15      


Tyr Leu Val Ser Gly Ser Pro Ile Met Asn Leu Glu Gln Ser Pro Leu 
            20                  25                  30          


Glu Glu Asp Met Ser Leu Phe Gly Asp Val Phe Ser Glu Gln Asp Gly 
        35                  40                  45              


Val Asp Phe Asn Thr Leu Leu Gln Ser Met Lys Asp Glu Phe Leu Lys 
    50                  55                  60                  


Thr Leu Asn Leu Ser Asp Ile Pro Thr Gln Asp Ser Ala Lys Val Asp 
65                  70                  75                  80  


Pro Pro Glu Tyr Met Leu Glu Leu Tyr Asn Lys Phe Ala Thr Asp Arg 
                85                  90                  95      


Thr Ser Met Pro Ser Ala Asn Ile Ile Arg Ser Phe Lys Asn Glu Asp 
            100                 105                 110         


Leu Phe Ser Gln Pro Val Ser Phe Asn Gly Leu Arg Lys Tyr Pro Leu 
        115                 120                 125             


Leu Phe Asn Val Ser Ile Pro His His Glu Glu Val Ile Met Ala Glu 
    130                 135                 140                 


Leu Arg Leu Tyr Thr Leu Val Gln Arg Asp Arg Met Ile Tyr Asp Gly 
145                 150                 155                 160 


Val Asp Arg Lys Ile Thr Ile Phe Glu Val Leu Glu Ser Lys Gly Asp 
                165                 170                 175     


Asn Glu Gly Glu Arg Asn Met Leu Val Leu Val Ser Gly Glu Ile Tyr 
            180                 185                 190         


Gly Thr Asn Ser Glu Trp Glu Thr Phe Asp Val Thr Asp Ala Ile Arg 
        195                 200                 205             


Arg Trp Gln Lys Ser Gly Ser Ser Thr His Gln Leu Glu Val His Ile 
    210                 215                 220                 


Glu Ser Lys His Asp Glu Ala Glu Asp Ala Ser Ser Gly Arg Leu Glu 
225                 230                 235                 240 


Ile Asp Thr Ser Ala Gln Asn Lys His Asn Pro Leu Leu Ile Val Phe 
                245                 250                 255     


Ser Asp Asp Gln Ser Ser Asp Lys Glu Arg Lys Glu Glu Leu Asn Glu 
            260                 265                 270         


Met Ile Ser His Glu Gln Leu Pro Glu Leu Asp Asn Leu Gly Leu Asp 
        275                 280                 285             


Ser Phe Ser Ser Gly Pro Gly Glu Glu Ala Leu Leu Gln Met Arg Ser 
    290                 295                 300                 


Asn Ile Ile Tyr Asp Ser Thr Ala Arg Ile Arg Arg Asn Ala Lys Gly 
305                 310                 315                 320 


Asn Tyr Cys Lys Arg Thr Pro Leu Tyr Ile Asp Phe Lys Glu Ile Gly 
                325                 330                 335     


Trp Asp Ser Trp Ile Ile Ala Pro Pro Gly Tyr Glu Ala Tyr Glu Cys 
            340                 345                 350         


Arg Gly Val Cys Asn Tyr Pro Leu Ala Glu His Leu Thr Pro Thr Lys 
        355                 360                 365             


His Ala Ile Ile Gln Ala Leu Val His Leu Lys Asn Ser Gln Lys Ala 
    370                 375                 380                 


Ser Lys Ala Cys Cys Val Pro Thr Lys Leu Glu Pro Ile Ser Ile Leu 
385                 390                 395                 400 


Tyr Leu Asp Lys Gly Val Val Thr Tyr Lys Phe Lys Tyr Glu Gly Met 
                405                 410                 415     


Ala Val Ser Glu Cys Gly Cys Arg 
            420                 


<210>  3
<211>  1290
<212>  DNA
<213>  Homo sapiens


<220>
<221>  CDS
<222>  (1)..(1290)

<400>  3
atg tgt cct ggg gca ctg tgg gtg gcc ctg ccc ctg ctg tcc ctg ctg         48
Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro Leu Leu Ser Leu Leu           
1               5                   10                  15                

gct ggc tcc cta cag ggg aag cca ctg cag agc tgg gga cga ggg tct         96
Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser           
            20                  25                  30                    

gct ggg gga aac gcc cac agc cca ctg ggg gtg cct gga ggt ggg ctg        144
Ala Gly Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu           
        35                  40                  45                        

cct gag cac acc ttc aac ctg aag atg ttt ctg gag aac gtg aag gtg        192
Pro Glu His Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val           
    50                  55                  60                            

gat ttc ctg cgc agc ctt aac ctg agt ggg gtc cct tcg cag gac aaa        240
Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys           
65                  70                  75                  80            

acc agg gtg gag ccg ccg cag tac atg att gac ctg tac aac agg tac        288
Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr           
                85                  90                  95                

acg tcc gat aag tcg act acg cca gcg tcc aac att gtg cgg agc ttc        336
Thr Ser Asp Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe           
            100                 105                 110                   

agc atg gaa gat gcc atc tcc ata act gcc aca gag gac ttc ccc ttc        384
Ser Met Glu Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe           
        115                 120                 125                       

cag aag cac atc ttg ctc ttc aac atc tcc att cct agg cat gag cag        432
Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln           
    130                 135                 140                           

atc acc aga gct gag ctc cga ctc tat gtc tcc tgt caa aat cac gtg        480
Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val           
145                 150                 155                 160           

gac ccc tct cat gac ctg aaa gga agc gtg gtc att tat gat gtt ctg        528
Asp Pro Ser His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu           
                165                 170                 175               

gat gga aca gat gcc tgg gat agt gct aca gag acc aag acc ttc ctg        576
Asp Gly Thr Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu           
            180                 185                 190                   

gtg tcc cag gac att cag gat gag ggc tgg gag acc ttg gaa gtg tcc        624
Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser           
        195                 200                 205                       

agc gcc gtg aag cgc tgg gtc cgg tcc gac tcc acc aag agc aaa aat        672
Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn           
    210                 215                 220                           

aag ctg gaa gtg act gtg gag agc cac agg aag ggc tgc gac acg ctg        720
Lys Leu Glu Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu           
225                 230                 235                 240           

gac atc agt gtc ccc cca ggt tcc aga aac ctg ccc ttc ttt gtt gtc        768
Asp Ile Ser Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val           
                245                 250                 255               

ttc tcc aat gac cac agc agt ggg acc aag gag acc agg ctg gag ctg        816
Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu           
            260                 265                 270                   

agg gag atg atc agc cat gaa caa gag agc gtg ctc aag aag ctg tcc        864
Arg Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser           
        275                 280                 285                       

aag gac ggc tcc aca gag gca ggt gag agc agt cac gag gag gac acg        912
Lys Asp Gly Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr           
    290                 295                 300                           

gat ggc cac gtg gct gcg ggg tcg act tta gcc agg cgg aaa agg agc        960
Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser           
305                 310                 315                 320           

gcc ggg gct ggc agc cac tgt caa aag acc tcc ctg cgg gta aac ttc       1008
Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe           
                325                 330                 335               

gag gac atc ggc tgg gac agc tgg atc att gca ccc aag gag tat gaa       1056
Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu           
            340                 345                 350                   

gcc tac gag tgt aag ggc ggc tgc ttc ttc ccc ttg gct gac gat gtg       1104
Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val           
        355                 360                 365                       

acg ccg acg aaa cac gct atc gtg cag acc ctg gtg cat ctc aag ttc       1152
Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe           
    370                 375                 380                           

ccc aca aag gtg ggc aag gcc tgc tgt gtg ccc acc aaa ctg agc ccc       1200
Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro           
385                 390                 395                 400           

atc tcc gtc ctc tac aag gat gac atg ggg gtg ccc acc ctc aag tac       1248
Ile Ser Val Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr           
                405                 410                 415               

cat tac gag ggc atg agc gtg gca gag tgt ggg tgc agg tag               1290
His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg                       
            420                 425                                       


<210>  4
<211>  429
<212>  PRT
<213>  Homo sapiens

<400>  4

Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro Leu Leu Ser Leu Leu 
1               5                   10                  15      


Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser 
            20                  25                  30          


Ala Gly Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu 
        35                  40                  45              


Pro Glu His Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val 
    50                  55                  60                  


Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys 
65                  70                  75                  80  


Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr 
                85                  90                  95      


Thr Ser Asp Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe 
            100                 105                 110         


Ser Met Glu Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe 
        115                 120                 125             


Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln 
    130                 135                 140                 


Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val 
145                 150                 155                 160 


Asp Pro Ser His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu 
                165                 170                 175     


Asp Gly Thr Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu 
            180                 185                 190         


Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser 
        195                 200                 205             


Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn 
    210                 215                 220                 


Lys Leu Glu Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu 
225                 230                 235                 240 


Asp Ile Ser Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val 
                245                 250                 255     


Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu 
            260                 265                 270         


Arg Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser 
        275                 280                 285             


Lys Asp Gly Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr 
    290                 295                 300                 


Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser 
305                 310                 315                 320 


Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe 
                325                 330                 335     


Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu 
            340                 345                 350         


Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val 
        355                 360                 365             


Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe 
    370                 375                 380                 


Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro 
385                 390                 395                 400 


Ile Ser Val Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr 
                405                 410                 415     


His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg 
            420                 425                 


<210>  5
<211>  429
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  D366A BMP9 variant

<400>  5

Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro Leu Leu Ser Leu Leu 
1               5                   10                  15      


Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser 
            20                  25                  30          


Ala Gly Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu 
        35                  40                  45              


Pro Glu His Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val 
    50                  55                  60                  


Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys 
65                  70                  75                  80  


Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr 
                85                  90                  95      


Thr Ser Asp Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe 
            100                 105                 110         


Ser Met Glu Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe 
        115                 120                 125             


Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln 
    130                 135                 140                 


Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val 
145                 150                 155                 160 


Asp Pro Ser His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu 
                165                 170                 175     


Asp Gly Thr Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu 
            180                 185                 190         


Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser 
        195                 200                 205             


Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn 
    210                 215                 220                 


Lys Leu Glu Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu 
225                 230                 235                 240 


Asp Ile Ser Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val 
                245                 250                 255     


Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu 
            260                 265                 270         


Arg Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser 
        275                 280                 285             


Lys Asp Gly Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr 
    290                 295                 300                 


Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser 
305                 310                 315                 320 


Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe 
                325                 330                 335     


Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu 
            340                 345                 350         


Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Ala Asp Val 
        355                 360                 365             


Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe 
    370                 375                 380                 


Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro 
385                 390                 395                 400 


Ile Ser Val Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr 
                405                 410                 415     


His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg 
            420                 425                 


<210>  6
<211>  429
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  D408A BMP9 variant

<400>  6

Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro Leu Leu Ser Leu Leu 
1               5                   10                  15      


Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser 
            20                  25                  30          


Ala Gly Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu 
        35                  40                  45              


Pro Glu His Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val 
    50                  55                  60                  


Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys 
65                  70                  75                  80  


Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr 
                85                  90                  95      


Thr Ser Asp Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe 
            100                 105                 110         


Ser Met Glu Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe 
        115                 120                 125             


Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln 
    130                 135                 140                 


Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val 
145                 150                 155                 160 


Asp Pro Ser His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu 
                165                 170                 175     


Asp Gly Thr Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu 
            180                 185                 190         


Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser 
        195                 200                 205             


Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn 
    210                 215                 220                 


Lys Leu Glu Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu 
225                 230                 235                 240 


Asp Ile Ser Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val 
                245                 250                 255     


Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu 
            260                 265                 270         


Arg Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser 
        275                 280                 285             


Lys Asp Gly Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr 
    290                 295                 300                 


Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser 
305                 310                 315                 320 


Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe 
                325                 330                 335     


Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu 
            340                 345                 350         


Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val 
        355                 360                 365             


Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe 
    370                 375                 380                 


Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro 
385                 390                 395                 400 


Ile Ser Val Leu Tyr Lys Asp Ala Met Gly Val Pro Thr Leu Lys Tyr 
                405                 410                 415     


His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg 
            420                 425                 


<210>  7
<211>  429
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  D366A/D408A double mutant BMP9 variant

<400>  7

Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro Leu Leu Ser Leu Leu 
1               5                   10                  15      


Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser 
            20                  25                  30          


Ala Gly Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu 
        35                  40                  45              


Pro Glu His Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val 
    50                  55                  60                  


Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys 
65                  70                  75                  80  


Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr 
                85                  90                  95      


Thr Ser Asp Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe 
            100                 105                 110         


Ser Met Glu Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe 
        115                 120                 125             


Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln 
    130                 135                 140                 


Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val 
145                 150                 155                 160 


Asp Pro Ser His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu 
                165                 170                 175     


Asp Gly Thr Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu 
            180                 185                 190         


Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser 
        195                 200                 205             


Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn 
    210                 215                 220                 


Lys Leu Glu Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu 
225                 230                 235                 240 


Asp Ile Ser Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val 
                245                 250                 255     


Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu 
            260                 265                 270         


Arg Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser 
        275                 280                 285             


Lys Asp Gly Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr 
    290                 295                 300                 


Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser 
305                 310                 315                 320 


Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe 
                325                 330                 335     


Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu 
            340                 345                 350         


Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Ala Asp Val 
        355                 360                 365             


Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe 
    370                 375                 380                 


Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro 
385                 390                 395                 400 


Ile Ser Val Leu Tyr Lys Asp Ala Met Gly Val Pro Thr Leu Lys Tyr 
                405                 410                 415     


His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg 
            420                 425                 


<210>  8
<211>  21
<212>  PRT
<213>  Homo sapiens


<220>
<221>  MISC_FEATURE
<222>  (1)..(21)
<223>  Transmembrane domain of BMPR-II

<400>  8

Ile Ile Ile Ala Leu Ala Ser Val Ser Val Leu Ala Val Leu Ile Val 
1               5                   10                  15      


Ala Leu Cys Phe Gly 
            20      


<210>  9
<211>  21
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  V158A mutant of human BMPR-II transmembrane domain

<400>  9

Ile Ile Ile Ala Leu Ala Ser Ala Ser Val Leu Ala Val Leu Ile Val 
1               5                   10                  15      


Ala Leu Cys Phe Gly 
            20      


<210>  10
<211>  21
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  V160A mutant of human BMPR-II transmembrane domain

<400>  10

Ile Ile Ile Ala Leu Ala Ser Val Ser Ala Leu Ala Val Leu Ile Val 
1               5                   10                  15      


Ala Leu Cys Phe Gly 
            20      


<210>  11
<211>  21
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  V163A mutant of human BMPR-II transmembrane domain

<400>  11

Ile Ile Ile Ala Leu Ala Ser Val Ser Val Leu Ala Ala Leu Ile Val 
1               5                   10                  15      


Ala Leu Cys Phe Gly 
            20      


<210>  12
<211>  21
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  V166A mutant of human BMPR-II transmembrane domain

<400>  12

Ile Ile Ile Ala Leu Ala Ser Val Ser Val Leu Ala Val Leu Ile Ala 
1               5                   10                  15      


Ala Leu Cys Phe Gly 
            20      


<210>  13
<211>  47
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  13
aataatcatt gctttggcat cagcctctgt attagctgtt ttgatag                     47


<210>  14
<211>  47
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  14
ctatcaaaac agctaataca gaggctgatg ccaaagcaat gattatt                     47


<210>  15
<211>  41
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  15
tgctttggca tcagtctctg cattagctgt tttgatagtt g                           41


<210>  16
<211>  41
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  16
caactatcaa aacagctaat gcagagactg atgccaaagc a                           41


<210>  17
<211>  43
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  17
catcagtctc tgtattagct gctttgatag ttgccttatg ctt                         43


<210>  18
<211>  43
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  18
aagcataagg caactatcaa agcagctaat acagagactg atg                         43


<210>  19
<211>  42
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  19
gtctctgtat tagctgtttt gatagctgcc ttatgctttg ga                          42


<210>  20
<211>  41
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  20
tccaaagcat aaggcagcta tcaaaacagt aatacagaga c                           41


<210>  21
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  21
gcaccacacc ttctacaatg a                                                 21


<210>  22
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  22
gtcatcttct cgcggttggc                                                   20


<210>  23
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  23
ttcgtatgac ggatcactcg                                                   20


<210>  24
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  24
agccctacat catggctgac                                                   20


<210>  25
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  25
ttctgctcct ctcctgggcg g                                                 21


<210>  26
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  26
gctcttttgg cacgctggtg t                                                 21


<210>  27
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  27
cacggcagag gggtgtgcaa                                                   20


<210>  28
<211>  22
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  28
tccggcagca agaagacaca gg                                                22


<210>  29
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  29
ggcactgagg agcagcaggc                                                   20


<210>  30
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  30
cggcctggga ccaactccct                                                   20


<210>  31
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  31
tagcagtgag tgcccgcctc c                                                 21


<210>  32
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  32
catagggcac acagcggcca g                                                 21


<210>  33
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  33
ctcgcgctac tctctctttc t                                                 21


<210>  34
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  34
cattctctgc tggatgacgt g                                                 21


<210>  35
<211>  24
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  35
caaatctgtg agcccaacag tcaa                                              24


<210>  36
<211>  29
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  36
gaggaagaat aatctggata aggaccaat                                         29


<210>  37
<211>  22
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  37
ggcggggaga ggaccatgtg ag                                                22


<210>  38
<211>  25
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  38
gaggcaggac tggtcttttt ccacg                                             25


<210>  39
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  39
ggaatccccc gtctacctct                                                   20


<210>  40
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  40
tgagcaagtg ctgagggttt                                                   20


<210>  41
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  41
ggctctaggt tccatgtccc                                                   20


<210>  42
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  42
agcagatccc tgcttctcaa                                                   20


<210>  43
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  43
gccatacaga tgccgacaga                                                   20


<210>  44
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  44
cagttaccga gctgccttga                                                   20


<210>  45
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  45
gacggccgag gcggcatg                                                     18


<210>  46
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  46
ggggagaccc acagagcacg                                                   20


<210>  47
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  47
cctagacctg gtggacaa                                                     18


<210>  48
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  48
acacagtcgt agcggttg                                                     18


<210>  49
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  49
cggaccatgt ctcccgcccc                                                   20


<210>  50
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  50
gtgactgggg tgagcgctgt g                                                 21


<210>  51
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  51
cttggcgtag cggccgaaga                                                   20


<210>  52
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  52
ctgggcggaa cgcatggtgg                                                   20


<210>  53
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  53
accttccacc gactgacccc a                                                 21


<210>  54
<211>  21
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  54
ggtacaccgc atcggggctt c                                                 21


<210>  55
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  55
gacaaggtgc gcgtctggca                                                   20


<210>  56
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  56
ctgggccacc gcgtcaaagt                                                   20


<210>  57
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  57
tcgctggttc tggcgtctgc                                                   20


<210>  58
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  58
gggtacccag gctccaccgt                                                   20


<210>  59
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  59
tccaccggga ccttcgtgca                                                   20


<210>  60
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  60
aatttggcac cttgccgcgc                                                   20


<210>  61
<211>  22
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  61
gcggccggag gacagatttg at                                                22


<210>  62
<211>  25
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  62
acggacatgg tgacactgta gtggg                                             25


<210>  63
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  63
agatctatcc tctccctaag                                                   20


<210>  64
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  64
ttagaatgga ctgccctgtc                                                   20


<210>  65
<211>  19
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  65
gtcgcaactg tgagagtga                                                    19


<210>  66
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  66
tcgcagaagg ctgtgttgat                                                   20


<210>  67
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  67
agcagactgg atgaaccgtg                                                   20


<210>  68
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  68
agctggaaag tcacgatggg                                                   20


<210>  69
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  69
gactgctcac tgaacgtgga                                                   20


<210>  70
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  70
cacaccggct gttgttgaag                                                   20


<210>  71
<211>  17
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  71
ctgcctgacg gtcaggt                                                      17


<210>  72
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  72
tggatgccac aggattccat                                                   20


<210>  73
<211>  25
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  73
tctgtgctaa tgatgatggc tctcc                                             25


<210>  74
<211>  23
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  74
ttcgcgatcc agggaaggat ttc                                               23


<210>  75
<211>  19
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  75
actgctgcag atggacctg                                                    19


<210>  76
<211>  19
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  76
agctccagtt cagagtccc                                                    19


<210>  77
<211>  26
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  77
agcacagaga ctctgaccta tttttg                                            26


<210>  78
<211>  23
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  78
ccacagattg ctagttgctg tga                                               23


<210>  79
<211>  19
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  79
cgacaccgga caaaccaaa                                                    19


<210>  80
<211>  22
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  80
gaatgtctgc cttctccagc tt                                                22


<210>  81
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  81
aagctgagat cttgcagatg                                                   20


<210>  82
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  82
ggcggcgaca gtttggag                                                     18


<210>  83
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  83
tgacatcctc catgtccc                                                     18


<210>  84
<211>  18
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Synthetic oligonucleotide

<400>  84
actgataacg gtgggctg                                                     18


