title: SerRS-tRNASec complex structures reveal mechanism of the first step in selenocysteine biosynthesis.
abstract: Selenocysteine (Sec) is found in the catalytic centers of many selenoproteins and plays important roles in living organisms. Malfunctions of selenoproteins lead to various human disorders including cancer. Known as the 21st amino acid, the biosynthesis of Sec involves unusual pathways consisting of several stages. While the later stages of the pathways are well elucidated, the molecular basis of the first stage-the serylation of Sec-specific tRNA (tRNA(Sec)) catalyzed by seryl-tRNA synthetase (SerRS)-is unclear. Here we present two cocrystal structures of human SerRS bound with tRNA(Sec) in different stoichiometry and confirm the formation of both complexes in solution by various characterization techniques. We discovered that the enzyme mainly recognizes the backbone of the long variable arm of tRNA(Sec) with few base-specific contacts. The N-terminal coiled-coil region works like a long-range lever to precisely direct tRNA 3' end to the other protein subunit for aminoacylation in a conformation-dependent manner. Restraints of the flexibility of the coiled-coil greatly reduce serylation efficiencies. Lastly, modeling studies suggest that the local differences present in the D- and T-regions as well as the characteristic U20:G19:C56 base triple in tRNA(Sec) may allow SerRS to distinguish tRNA(Sec) from closely related tRNA(Ser) substrate.
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China Center for Cellular & Structural biology, The Sun Yat-Sen University, 132 E. Circle Rd., University City, Guangzhou, Guangdong 510006, People's Republic of China.
authors.forename: Caiyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China Center for Cellular & Structural biology, The Sun Yat-Sen University, 132 E. Circle Rd., University City, Guangzhou, Guangdong 510006, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China Center for Cellular & Structural biology, The Sun Yat-Sen University, 132 E. Circle Rd., University City, Guangzhou, Guangdong 510006, People's Republic of China.
authors.forename: Qingnan
authors.initials: Q
authors.lastname: Tian
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China Center for Cellular & Structural biology, The Sun Yat-Sen University, 132 E. Circle Rd., University City, Guangzhou, Guangdong 510006, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jia
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China.
authors.forename: Yuanzhu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China.
authors.forename: Qinfen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 430 E. 67th Street, New York, NY 10065, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510275, People's Republic of China Center for Cellular & Structural biology, The Sun Yat-Sen University, 132 E. Circle Rd., University City, Guangzhou, Guangdong 510006, People's Republic of China xiewei6@mail.sysu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
mesh_terms: D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012345:RNA, Transfer, Amino Acid-Specific / Q000737:chemistry* / Q000378:metabolism; D017279:Selenocysteine / Q000096:biosynthesis*; D012714:Serine-tRNA Ligase / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D012345:RNA, Transfer, Amino Acid-Specific; C036928:tRNA, selenocysteine-; D017279:Selenocysteine; D012714:Serine-tRNA Ligase