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Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Arnold, Laurence H 
Groom, Harriet CT 
Kunzelmann, Simone 
Schwefel, David 
Caswell, Sarah J 

Abstract

SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural and virological data demonstrating that in addition to allosteric activation and triphosphohydrolase activity, restriction correlates with the capacity of SAMHD1 to form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes restriction but has varied effects on in vitro triphosphohydrolase activity. SAMHD1 phosphorylation also ablates restriction and tetramer formation but without affecting triphosphohydrolase steady-state kinetics. However phospho-SAMHD1 is unable to catalyse dNTP turnover under conditions of nucleotide depletion. Based on our findings we propose a model for phosphorylation-dependent regulation of SAMHD1 activity where dephosphorylation switches housekeeping SAMHD1 found in cycling cells to a high-activity stable tetrameric form that depletes and maintains low levels of dNTPs in differentiated cells.

Description

Keywords

Biocatalysis, Cell Line, Chromatography, Gel, Chromatography, High Pressure Liquid, Crystallography, X-Ray, Flow Cytometry, HIV-1, Humans, Monomeric GTP-Binding Proteins, Phosphorylation, Protein Conformation, Reverse Transcriptase Polymerase Chain Reaction, SAM Domain and HD Domain-Containing Protein 1, Spectrophotometry, Atomic

Journal Title

PLoS Pathog

Conference Name

Journal ISSN

1553-7366
1553-7374

Volume Title

11

Publisher

Public Library of Science (PLoS)