A putative cyclin-binding motif in human SAMHD1 contributes to protein phosphorylation, localization, and stability

Corine St Gelais, Sun Hee Kim, Lingmei Ding, Jacob S. Yount, Dmitri Ivanov, Paul Spearman, Li Wu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

SAMHD1 (sterile α motif and HD domain-containing protein 1) is a mammalian protein that regulates intracellular dNTP levels through its hydrolysis of dNTPs. SAMHD1 functions as an important retroviral restriction factor through a mechanism relying on its dNTPase activity. We and others have reported that human SAMHD1 interacts with the cell cycle regulatory proteins cyclin A, CDK1, and CDK2, which mediates phosphorylation of SAMHD1 at threonine 592, a post-translational modification that has been implicated in abrogating SAMHD1 restriction function and ability to form stable tetramers. Utilizing co-immunoprecipitation and colocalization approaches, we show that endogenous SAMHD1 is able to interact with the cyclin A-CDK1-CDK2 complex in monocytic THP-1 cells and primary monocyte-derived macrophages. Sequence analysis of SAMHD1 identifies a putative cyclin-binding motif found in many cyclin-CDK complex substrates. Using a mutagenesis-based approach, we demonstrate that the conserved residues in the putative cyclin-binding motif are important for protein expression, protein half-life, and optimal phosphorylation of SAMHD1 at Thr592. Furthermore, we observed that SAMHD1 mutants of the cyclin-binding motif mislocalized to a nuclear compartment and had reduced ability to interact with cyclin A-CDK complexes and to form the tetramer. These findings help define the mechanisms by which SAMHD1 is phosphorylated and suggest the contribution of cyclin binding to SAMHD1 expression and stability in dividing cells.

Original languageEnglish (US)
Pages (from-to)26332-26342
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number51
DOIs
StatePublished - Dec 16 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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