The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Olga Buzovetsky; Chenxiang Tang; Kirsten M Knecht; Jenna M Antonucci; Li Wu; Xiaoyun Ji; Yong Xiong

doi:10.1038/s41467-017-02783-8

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The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Journal article

Open access

Peer reviewed

The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Olga Buzovetsky, Chenxiang Tang, Kirsten M Knecht, Jenna M Antonucci, Li Wu, Xiaoyun Ji and Yong Xiong

Nature communications, Vol.9(1), 411

01/29/2018

DOI: 10.1038/s41467-017-02783-8

PMCID: PMC5788916

PMID: 29379009

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Abstract

Human SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. SAMHD1 is allosterically activated by nucleotides that induce assembly of the active tetramer. Although the catalytic core of hSAMHD1 has been studied extensively, previous structures have not captured the regulatory SAM domain. Here we report the crystal structure of full-length SAMHD1 by capturing mouse SAMHD1 (mSAMHD1) structures in three different nucleotide bound states. Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we find that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide insights into the regulation of SAMHD1 activity, thereby facilitating the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.

Hydrolysis

Animals

SAM Domain and HD Domain-Containing Protein 1 - metabolism

Protein Multimerization

Allosteric Site

Models, Molecular

Protein Domains

Crystallography, X-Ray

Mice

SAM Domain and HD Domain-Containing Protein 1 - genetics

SAM Domain and HD Domain-Containing Protein 1 - chemistry

Details

Title: Subtitle: The SAM domain of mouse SAMHD1 is critical for its activation and regulation
Creators: Olga Buzovetsky - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA
Chenxiang Tang - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA
Kirsten M Knecht - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA
Jenna M Antonucci - Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA
Li Wu - Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA
Xiaoyun Ji - The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China. xiaoyun.ji@nju.edu.cn
Yong Xiong - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. yong.xiong@yale.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), 411
DOI: 10.1038/s41467-017-02783-8
PMID: 29379009
PMCID: PMC5788916
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 AI102778 / NIAID NIH HHS R01 AI104483 / NIAID NIH HHS T32 GM007223 / NIGMS NIH HHS K99 AI120845 / NIAID NIH HHS T32 GM008283 / NIGMS NIH HHS
Language: English
Date published: 01/29/2018
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001108002771

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