title: Mechanism of allosteric activation of SAMHD1 by dGTP.
abstract: SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutières syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS.
authors.affiliation: 1] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. [2].
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Ji
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Junpeng
authors.initials: J
authors.lastname: Yan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mehrens
authors.forename: Haitao
authors.initials: H
authors.lastname: Yang
authors.forename: Maria
authors.initials: M
authors.lastname: DeLucia
authors.forename: Caili
authors.initials: C
authors.lastname: Hao
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
authors.forename: Jacek
authors.initials: J
authors.lastname: Skowronski
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003848:Deoxyguanine Nucleotides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D003848:Deoxyguanine Nucleotides; C029603:deoxyguanosine triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins