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

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 mous...

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Bibliographic Details
Published in:Cell 2023-06, Vol.186 (13), p.2897-2910.e19
Main Authors: Zhou, Lunni, Liu, Haobin, Liu, Siyu, Yang, Xiaoyu, Dong, Yue, Pan, Yun, Xiao, Zhuang, Zheng, Beihong, Sun, Yan, Huang, Pengyu, Zhang, Xixi, Hu, Jin, Sun, Rui, Feng, Shan, Zhu, Yi, Liu, Mingxi, Gui, Miao, Wu, Jianping
Format: Article
Language:English
Subjects:
asthenozoospermia
cryo-EM
doublet microtubule
FAM166 family
male infertility
microtubule inner proteins
sperm flagella
sperm motility
Tektin5
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Summary: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. [Display omitted] •Cryo-EM structure of the mouse sperm DMT reveals 10 sperm-specific MIPs•Sperm DMTs feature a polymorphic Tektin5 network and multiple FAM166 proteins•The human sperm DMT has fewer MIPs compared with the mouse sperm DMT•MIP variants are associated with a subtype of asthenozoospermia we termed MIVA Cryo-EM and AI-based analyses of mouse and human sperm double microtubules provide fresh insights into the genetic basis of sperm motility and male infertility.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2023.05.009