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.
journal_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Arnold LH,Groom HC,Kunzelmann S,Schwefel D,Caswell SJ,Ordonez P,Mann MC,Rueschenbaum S,Goldstone DC,Pennell S,Howell SA,Stoye JP,Webb M,Taylor IA,Bishop KNdoi
10.1371/journal.ppat.1005194subject
Has Abstractpub_date
2015-10-02 00:00:00pages
e1005194issue
10eissn
1553-7366issn
1553-7374pii
PPATHOGENS-D-15-00764journal_volume
11pub_type
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