title: Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile α-Motif/Histidine-Aspartate Domain-containing Protein.
abstract: Sterile α-motif/histidine-aspartate domain-containing protein (SAMHD1), a homo-tetrameric GTP/dGTP-dependent dNTP triphosphohydrolase, catalyzes the conversion of dNTP into deoxynucleoside and triphosphate. As the only characterized dNTP triphosphohydrolase in human cells, SAMHD1 plays an important role in human innate immunity, autoimmunity, and cell cycle control. Previous biochemical studies and crystal structures have revealed that SAMHD1 interconverts between an inactive monomeric or dimeric form and a dGTP/GTP-induced active tetrameric form. Here, we describe a novel state of SAMHD1 (109-626 amino acids, SAMHD1C) that is characterized by a rapid initial hydrolysis rate. Interestingly, the crystal structure showed that this novel SAMHD1 tetramer contains only GTP and has structural features distinct from the GTP/dNTP-bound SAMHD1 tetramer. Our work thus reveals structural features of SAMHD1 that may represent one of its biological assembly states in cells. The biochemical and structural information generated by the present study not only provides an ordered pathway for the assembly and activation of SAMHD1 but also provides insights into the potential mechanisms of the high-efficiency catalytic activity of this enzyme family in vivo.
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and.
authors.forename: Jia
authors.initials: J
authors.lastname: Kong
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and.
authors.forename: Xin
authors.initials: X
authors.lastname: Peng
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and nkqinxiaohong@126.com.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Qin
authors.affiliation: From the School of Life Sciences, Tianjin University, Tianjin 300072 and the Institute of Virology and AIDS Research, First Hospital of Jilin University, 519 East Minzhu Avenue, Changchun 130061, Jilin Province, China yuxiaofang@jlu.edu.cn.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D002453:Cell Cycle; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D000076106:SAM Domain and HD Domain-Containing Protein 1; D017386:Sequence Homology, Amino Acid
chemical_list: D011994:Recombinant Proteins; D001224:Aspartic Acid; D006639:Histidine; D006160:Guanosine Triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: SAM domain- and HD domain-containing protein 1 (SAMHD1); dNTPase; enzyme catalysis; human immunodeficiency virus (HIV); innate immunity; lentivirus; restriction factor