Structures of sperm flagellar doublet microtubules expand the genetic spectrum of male infertility.

Journal: Cell
PMID: 37295417

Abstract

Sperm motility is crucial for successful fertilization. Highly decorated doublet microtubules (DMTs) form the sperm tail skeleton, which propels the movement of spermatozoa. Using cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-based modeling, we determined the structures of mouse and human sperm DMTs and built an atomic model of the 48-nm repeat of the mouse sperm DMT. Our analysis revealed 47 DMT-associated proteins, including 45 microtubule inner proteins (MIPs). We identified 10 sperm-specific MIPs, including seven classes of Tektin5 in the lumen of the A tubule and FAM166 family members that bind the intra-tubulin interfaces. Interestingly, the human sperm DMT lacks some MIPs compared with the mouse sperm DMT. We also discovered variants in 10 distinct MIPs associated with a subtype of asthenozoospermia characterized by impaired sperm motility without evident morphological abnormalities. Our study highlights the conservation and tissue/species specificity of DMTs and expands the genetic spectrum of male infertility.

Authors

  • Lunni Zhou
    Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China.
  • Haobin Liu
    Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China.
  • Siyu Liu
    Citromax Flavors Group, Inc., 444 Washington Ave, Carlstadt, NJ, 07072, USA.
  • Xiaoyu Yang
    Beijing Jishuitan Hospital, Beijing, China.
  • Yue Dong
    Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, United States.
  • Yun Pan
    School of Computer and Cyberspace Security, Communication University of China, Beijing 100024, China.
  • Zhuang Xiao
    State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • Beihong Zheng
    Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China.
  • Yan Sun
    Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, United States.
  • Pengyu Huang
    University of Southern California, Los Angeles, California, USA.
  • Xixi Zhang
    Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China.
  • Jin Hu
    Department of Mathematics, Chongqing Jiaotong University, Chongqing, China. Electronic address: windyvictor@gmail.com.
  • Rui Sun
    The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
  • Shan Feng
    Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China.
  • Yi Zhu
    2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong China.
  • Mingxi Liu
    State Key Laboratory of Reproductive Medicine and Offspring Health, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: mingxi.liu@njmu.edu.cn.
  • Miao Gui
    Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China. Electronic address: miaogui@zju.edu.cn.
  • Jianping Wu
    Department of Civil Engineering, Tsinghua University, Beijing, 100084, China.

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