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

doi:10.1074/jbc.m116.753947

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A Putative Cyclin-binding Motif in Human SAMHD1 Contributes to Protein Phosphorylation, Localization, and Stability

Journal article

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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 and Li Wu

The Journal of biological chemistry, Vol.291(51), pp.26332-26342

12/16/2016

DOI: 10.1074/jbc.m116.753947

PMCID: PMC5159495

PMID: 27815502

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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 co-localization approaches, we show that endogenous SAMHD1 is able to interact with the cyclin A-CDK1-CDK2 complexin 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 Thr 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.

Phosphorylation - physiology

CDC2 Protein Kinase

Cyclin-Dependent Kinase 2 - metabolism

Cyclin-Dependent Kinases - metabolism

Monocytes - cytology

Cyclin A - metabolism

Humans

SAM Domain and HD Domain-Containing Protein 1

Cyclin-Dependent Kinase 2 - genetics

Monocytes - metabolism

Cyclin A - genetics

Macrophages - cytology

Monomeric GTP-Binding Proteins - genetics

Protein Processing, Post-Translational - physiology

Cell Division - physiology

Macrophages - metabolism

Monomeric GTP-Binding Proteins - biosynthesis

Cell Line, Tumor

Cyclin-Dependent Kinases - genetics

Details

Title: Subtitle: A Putative Cyclin-binding Motif in Human SAMHD1 Contributes to Protein Phosphorylation, Localization, and Stability
Creators: Corine St Gelais - From the Center of Retrovirus Research, Department of Veterinary Biosciences and
Sun Hee Kim - From the Center of Retrovirus Research, Department of Veterinary Biosciences and
Lingmei Ding - the Department of Pediatrics, Emory University, Atlanta, Georgia 30322
Jacob S Yount - the Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio 43210
Dmitri Ivanov - the Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229
Paul Spearman - Children's Healthcare of Atlanta, Atlanta, Georgia 30322, and
Li Wu - the Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio 43210
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.291(51), pp.26332-26342
DOI: 10.1074/jbc.m116.753947
PMID: 27815502
PMCID: PMC5159495
NLM abbreviation: J Biol Chem
ISSN: 1083-351X
eISSN: 1083-351X
Publisher: United States
Grant note: R01 AI104483 / NIAID NIH HHS R21 CA181997 / NCI NIH HHS R01 AI104476 / NIAID NIH HHS R01 AI120209 / NIAID NIH HHS R01 GM111027 / NIGMS NIH HHS
Language: English
Date published: 12/16/2016
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001120502771

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