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Structural characterization and biological function of bivalent binding of CD2AP to intrinsically disordered domain of chikungunya virus nsP3 protein

Journal article
Authors P. Agback
F. Dominguez
Yulia Pustovalova
T. Lukash
N. Shiliaev
Vladislav Orekhov
I. Frolov
T. Agback
E. I. Frolova
Published in Virology
Volume 537
Pages 130-142
ISSN 0042-6822
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Pages 130-142
Language en
Subject categories Virology, Clinical virology


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. © 2019 Elsevier Inc.

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