Structural characterization and biological function of bivalent binding of CD2AP to intrinsically disordered domain of chikungunya virus nsP3 protein.
Virology
; 537: 130-142, 2019 11.
Article
em En
| MEDLINE
| ID: mdl-31493651
ABSTRACT
Alphavirus nsP3 proteins contain long, intrinsically disordered, hypervariable domains, HVD, which serve as hubs for interaction with many cellular proteins. Here, we have deciphered the mechanism and function of HVD interaction with host factors in alphavirus replication. Using NMR spectroscopy, we show that CHIKV HVD contains two SH3 domain-binding sites. Using an innovative chemical shift perturbation signature approach, we demonstrate that CD2AP interaction with HVD is mediated by its SH3-A and SH3-C domains, and this leaves the SH3-B domain available for interaction with other cellular factor(s). This cooperative interaction with two SH3 domains increases binding affinity to CD2AP and possibly induces long-range allosteric effects in HVD. Our data demonstrate that BIN1, CD2AP and SH3KBP1 play redundant roles in initiation of CHIKV replication. Point mutations in both CHIKV HVD binding sites abolish its interaction with all three proteins, CD2AP, BIN1 and SH3KBP1. This results in strong inhibition of viral replication initiation.
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Base de dados:
MEDLINE
Assunto principal:
Replicação Viral
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Vírus Chikungunya
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Proteínas não Estruturais Virais
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Proteínas do Citoesqueleto
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Proteínas Adaptadoras de Transdução de Sinal
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Interações Hospedeiro-Patógeno
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article