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PDBsum entry 5ao3
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References listed in PDB file
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Key reference
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Title
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Phospho-Dependent regulation of samhd1 oligomerisation couples catalysis and restriction.
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Authors
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L.H.Arnold,
H.C.Groom,
S.Kunzelmann,
D.Schwefel,
S.J.Caswell,
P.Ordonez,
M.C.Mann,
S.Rueschenbaum,
D.C.Goldstone,
S.Pennell,
S.A.Howell,
J.P.Stoye,
M.Webb,
I.A.Taylor,
K.N.Bishop.
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Ref.
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Plos Pathog, 2015,
11,
e1005194.
[DOI no: ]
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PubMed id
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Abstract
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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.
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