{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:41:31Z","timestamp":1779882091428,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,15]]},"group-title":"Biochemistry","reference-count":29,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R00HD104924"],"award-info":[{"award-number":["R00HD104924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>TMEM95 is a sperm acrosomal membrane protein essential for mammalian fertilization. How TMEM95 facilitates sperm\u2013egg interaction has largely remained unknown. Analogous sperm fertilization proteins function as complexes, leading us to hypothesize that TMEM95 may have a binding partner on sperm. Here, we surveyed interactions between TMEM95 and individual proteins in a curated library of testis-expressed proteins using AlphaFold3. We identify FIMP, a fertilization-essential acrosomal membrane protein, as a high-confidence interaction partner of TMEM95. These two proteins form a high-affinity complex through their ectodomains. Using single-particle cryo-EM, we determine the structure of the human TMEM95\u2013FIMP ectodomain complex at high resolution. An aromatic motif of FIMP binds to a conserved surface of TMEM95, and amino acid substitutions within this motif ablate the TMEM95-binding activity of FIMP. We isolate an anti-TMEM95 antibody, termed 3A02, that binds to human and murine TMEM95 and disrupts the interaction between TMEM95 and FIMP. By determining the cryo-EM structure of human TMEM95 bound to the 3A02 fragment antigen-binding region, we find that 3A02 recognizes the FIMP-binding site on TMEM95. 3A02 inhibits fusion of murine sperm with eggs, independent of antibody size, suggesting that the TMEM95\u2013FIMP interface is critical for sperm\u2013egg interaction. Together, these results establish the human sperm TMEM95\u2013FIMP complex and suggest that a FIMP-mediated interaction of TMEM95 facilitates membrane fusion during mammalian fertilization.<\/jats:p>","DOI":"10.64898\/2026.05.14.724122","type":"posted-content","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T03:35:15Z","timestamp":1778902515000},"source":"Crossref","is-referenced-by-count":2,"title":["Structure and inhibition of the sperm TMEM95\u2013FIMP complex in mammalian fertilization"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0046-6997","authenticated-orcid":false,"given":"Pulan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0034-9902","authenticated-orcid":false,"given":"Rithik 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