Advertisement

 

 

Allosteric Signal Transduction in HIV-1 Restriction Factor SAMHD1 proceeds via Reciprocal Handshake across Monomers.

Allosteric Signal Transduction in HIV-1 Restriction Factor SAMHD1 proceeds via Reciprocal Handshake across Monomers.
Author Information (click to view)

Patra KK, Bhattacharya A, Bhattacharya S,


Patra KK, Bhattacharya A, Bhattacharya S, (click to view)

Patra KK, Bhattacharya A, Bhattacharya S,

Advertisement

Journal of chemical information and modeling 2017 09 28() doi 10.1021/acs.jcim.7b00279

Abstract

The sterile alpha motif and histidine-aspartate domain-containing protein 1 (or SAMHD1), a human dNTP-triphosphohydrolase, contributes to HIV-1 restriction in select terminally differentiated cells of the immune system. The catalytically active form of the protein is an allosterically triggered tetramer, whose HIV-1 restriction properties are attributed to its dNTP – triphosphohydrolase activity. The tetramer itself is assembled by a GTP/dNTP combination. This enzyme uses the strategy of deoxynucleotide starvation, which is thought to prevent effective reverse transcription of the retroviral genome – hence restricting HIV-1 propagation. HIV-2 and SIV have evolved defences against SAMHD1, underscoring its role in restriction. Previous studies have provided high-resolution structures of GTP/dNTP bound enzyme complexes, but have not been able to provide information on dynamics. In this study, we have used correlation network analysis along with MD techniques to study the flow of allosteric information across the active complex. We have found evidence of a reciprocal allosteric "handshake" occurring across monomeric units. We have also uncovered a short linker region as the nexus for funnelling the regulatory signal from phosphorylation at T592 from the surface to the interior core of the protein.

Submit a Comment

Your email address will not be published. Required fields are marked *

four × 5 =

[ HIDE/SHOW ]