title: SEPT12 orchestrates the formation of mammalian sperm annulus by organizing core octameric complexes with other SEPT proteins.
abstract: Male infertility has become a worldwide health problem, but the etiologies of most cases are still unknown. SEPT12, a GTP-binding protein, is involved in male fertility. Two SEPT12 mutations (SEPT12(T89M) and SEPT12(D197N)) have been identified in infertile men who have a defective sperm annulus with a bent tail. The function of SEPT12 in the sperm annulus is still unclear. Here, we found that SEPT12 formed a filamentous structure with SEPT7, SEPT 6, SEPT2 and SEPT4 at the sperm annulus. The SEPT12-based septin core complex was assembled as octameric filaments comprising the SEPT proteins 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12. In addition, the GTP-binding domain of SEPT12 was crucial for its interaction with SEPT7, and the N- and C-termini of SEPT12 were required for the interaction of SEPT12 with itself to polymerize octamers into filaments. Mutant mice carrying the SEPT12(D197N) mutation, which disrupts SEPT12 filament formation, showed a disorganized sperm annulus, bent tail, reduced motility and loss of the SEPT ring structure at the sperm annulus. These phenotypes were also observed in an infertile man carrying SEPT12(D197N). Taken together, our results demonstrate the molecular architecture of SEPT12 filaments at the sperm annulus, their mechanical support of sperm motility, and their correlation with male infertility.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.
authors.forename: Yung-Che
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
authors.forename: Hau-Inh
authors.initials: HI
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yet-Ran
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.
authors.forename: Chia-Yih
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan paolink@mail.ncku.edu.tw.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D013081:Sperm Motility; D013082:Sperm Tail / Q000378:metabolism*
chemical_list: C555146:SEPT12 protein, mouse; C502729:SEPTIN12 protein, human; D058112:Septins
keywords: SEPT12; Septin octamer; Sperm annulus; Spermiogenesis