Signatures  of  pleiotropy,  economy  and    convergent  evolu6on  in  a  domain-­‐resolved  map  of  human-­‐virus  protein-­‐protein  interac6on  networks  

Yu  (Brandon)  Xia  Department  of  Bioengineering  

McGill  University  

Eric  Franzosa  Sara  Garamszegi  

Between-­‐species  systems  biology  

HH

H

H

H

H

H

H

H

V H HumanProtein

VirusProtein

SequenceHomology

KnownInteraction

StableComplex

V HH

HHV

HH

HV

(a) (b) (c)

V  

V  

V   V  

•  Within-­‐human  PPI  network:  endogenous  •  Human-­‐virus  PPI  network:  exogenous  

2  [Uetz,  2006;  Calderwood,  2007;  Dyer,  2008;  etc.]  

Between-­‐species  structural  systems  biology  

HH

H

H

H

H

H

H

H

V H HumanProtein

VirusProtein

SequenceHomology

KnownInteraction

StableComplex

V HH

HHV

HH

HV

(a) (b) (c)

V  

V  

V   V  

•  Within-­‐human  PPI  network:  endogenous  •  Human-­‐virus  PPI  network:  exogenous  

3  

Template-­‐based  modeling  

[Franzosa  and  Xia,  PNAS  2011]  

Within-­‐human  and  human-­‐virus  structural  interac6on  networks  

53  exogenous  interac6ons  3,039  endogenous  interac6ons  

4  

[Franzosa  and  Xia,  PNAS  2011]  

Virus  proteins  tend  to  bind  to  exis6ng  endogenous  interfaces  

[Franzosa  and  Xia,  PNAS  2011]   5  

H  H  

V  

Proper6es  of  mimicked  interfaces  

•  Endogenous  interfaces  mimicked  by  virus  proteins  tend  to  involve  regulatory  ac6vi6es,  transient  binding,  and  parWcipate  in  mul6ple  endogenous  interac6ons  

•  Viruses  target  high-­‐level,  regulatory  components  of  the  cellular  circuitry  6  

H  H  

H  

H  H  

V  H   H  

V  

H  H  

H  

V  

H  

[Franzosa  and  Xia,  PNAS  2011]  

Viral  binding  accelerates  endogenous  interface  evolu6on  

[Franzosa  and  Xia,  PNAS  2011]   7  

8  

Two  types  of  protein-­‐protein  interac6ons  

Domain-­‐domain  interac6on    Domain-­‐mo6f  interac6on  

9  

Case  studies  

[Davey,  Travé,  Gibson,  Trends  Biochem  Sci  2011]  

10  

A  domain-­‐resolved  map  of  human-­‐human  and  human-­‐virus  protein-­‐protein  interac6on  networks  

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

11  

Domain-­‐resolved  interac6ons  are  of  high  quality  

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

12  

Binding  site  mimicry  evolves  differently  in  virus  and  human  proteins  

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

13  

Viral  proteins  tend  to  target  human  proteins  containing  linear  mo6f-­‐binding  (LMB)  domains    

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

14  

Viruses  tend  to  target  human  proteins  containing  LMB  domains,  independent  of  host  protein  degree    

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

15  

Viral  proteins  have  a  higher  frac6on  of  domain-­‐mo6f  interac6ons  than  human  proteins  

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

16  

Viral  proteins  target  LMB  domains  at  greater  density  than  human  proteins  

[Garamszegi,  Franzosa,  Xia,  PLoS  Pathogens  2013]  

Our  domain-­‐resolved  network  

CCSB  interactome  network  

Three  design  principles  of  the  domain-­‐resolved  human-­‐virus  protein-­‐protein  interac6on  network  

•  Human-­‐virus  PPI  network  is  antagonis6c  

•  Human-­‐virus  PPI  network  is  economical  

•  Human-­‐virus  PPI  network  is  strongly  shaped  by  convergent  evolu6on  

•  Most  of  these  signatures  are  only  apparent  at  high  resoluWon  

17  

Acknowledgments  

•  Eric  Franzosa  •  Chetanya  Pandya    

•  KonstanWn  Voevodski  •  Jignesh  Parikh  •  Han  Hu    

•  Yong  Wang  •  Jasmin  Coulombe-­‐HunWngton  •  Christopher  Jacobs  

•  Bolan  Linghu    •  Sara  Garamszegi  •  Alexandra  Dumitriu  

•  Ran  Xue  •  Qingyu  Gao  •  Sachit  Bakshi  •  Kevin  Lynagh  •  Javier  Pérez-­‐Florido        

18  

Funding