Human sperm TMEM95 binds eggs and facilitates membrane fusion.
Human sperm TMEM95 binds eggs and facilitates membrane fusion.
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人类精子 TMEM95 结合卵子并促进膜融合。
DOI：
10.1073/pnas.2207805119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
精子和卵子的膜融合在有性生殖中起着关键作用。TMEM95基因敲除小鼠产生的精子可以与卵子结合，但不能与卵子融合。TMEM95如何促进膜融合尚不清楚。我们在这里展示了人类TMEM95结合卵子。我们的TMEM95的晶体结构表明可能发生这种结合的区域。我们开发了针对TMEM95的单抗，它会损害精子-卵子的融合，但不会阻止精子-卵子的结合。因此，我们认为精子TMEM95与卵子之间存在受体介导的相互作用，这种相互作用可能在膜融合中起直接作用。我们的工作为鉴定TMEM95卵子受体以及开发人类不孕不育治疗和避孕药物提供了途径。TMEM95编码一种精子顶体膜蛋白，其敲除的基因在小鼠中具有男性特有的不育表型。TMEM95基因敲除的小鼠精子可以与卵子结合，但不能与卵子融合。TMEM95如何在精子和卵子的膜融合中发挥作用仍然是个谜。在这里，我们利用精子穿透试验作为模型系统来研究人类TMEM95的功能。我们发现人TMEM95与仓鼠卵膜结合，为卵子上存在TMEM95受体提供了证据。利用X射线结晶学，我们揭示了TMEM95的一个进化保守的正电区作为假定的受体结合表面。TMEM95这一区域内的氨基酸取代会削弱鸡蛋结合活性。我们确定了抗TMEM95的单抗，它可以减少精子穿透试验中与仓鼠卵子融合的人类精子的数量。引人注目的是，这些抗体不会阻止精子与卵子的结合。综上所述，这些结果为精子TMEM95与卵子的特异性受体介导的相互作用提供了强有力的证据，并表明这种相互作用可能在促进受精过程中的膜融合方面发挥作用。
Membrane fusion of sperm and eggs is pivotal in sexual reproduction. Tmem95 knockout mice produce sperm that can bind to, but do not fuse with, eggs. How TMEM95 facilitates membrane fusion was unknown. We show here that human TMEM95 binds eggs. Our crystal structure of TMEM95 suggests a region where this binding may occur. We develop monoclonal antibodies against TMEM95 that impair sperm-egg fusion but do not block sperm-egg binding. Thus, we propose that there is a receptor-mediated interaction of sperm TMEM95 with eggs, and that this interaction may have a direct role in membrane fusion. Our work suggests avenues for the identification of the TMEM95 egg receptor and the development of infertility treatments and contraceptives for humans. Tmem95 encodes a sperm acrosomal membrane protein, whose knockout has a male-specific sterility phenotype in mice. Tmem95 knockout murine sperm can bind to, but do not fuse with, eggs. How TMEM95 plays a role in membrane fusion of sperm and eggs has remained elusive. Here, we utilize a sperm penetration assay as a model system to investigate the function of human TMEM95. We show that human TMEM95 binds to hamster egg membranes, providing evidence for a TMEM95 receptor on eggs. Using X-ray crystallography, we reveal an evolutionarily conserved, positively charged region of TMEM95 as a putative receptor-binding surface. Amino acid substitutions within this region of TMEM95 ablate egg-binding activity. We identify monoclonal antibodies against TMEM95 that reduce the number of human sperm fused with hamster eggs in sperm penetration assays. Strikingly, these antibodies do not block binding of sperm to eggs. Taken together, these results provide strong evidence for a specific, receptor-mediated interaction of sperm TMEM95 with eggs and suggest that this interaction may have a role in facilitating membrane fusion during fertilization.
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影响因子：
5.9
作者：
Noda T;Blaha A;Fujihara Y;Gert KR;Emori C;Deneke VE;Oura S;Panser K;Lu Y;Berent S;Kodani M;Cabrera-Quio LE;Pauli A;Ikawa M
通讯作者：
Ikawa M
影响因子：
4.5
作者：
Pausch H;Kölle S;Wurmser C;Schwarzenbacher H;Emmerling R;Jansen S;Trottmann M;Fuerst C;Götz KU;Fries R
通讯作者：
Fries R
影响因子：
30.8
作者：
Kaji, K;Oda, S;Kudo, A
通讯作者：
Kudo, A
DOI：
10.1126/science.aad6887
发表时间：
2016-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Miller MR;Mannowetz N;Iavarone AT;Safavi R;Gracheva EO;Smith JF;Hill RZ;Bautista DM;Kirichok Y;Lishko PV
通讯作者：
Lishko PV
影响因子：
64.8
作者：
Aydin H;Sultana A;Li S;Thavalingam A;Lee JE
通讯作者：
Lee JE