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Increasing evidence suggests microvilli are mechanosensitive, but underlying molecules and mechanisms remain unknown. Here, we localize transmembrane channel-like proteins 4 and 5 (TMC4 and 5) and calcium and integrin binding protein 3 (CIB3) to microvillar tips in intestinal epithelial cells, near glycocalyx insertion sites. We find that TMC5 colocalizes with CIB3 in cultured cells and that a TMC5 fragment forms a complex with CIB3\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Homology and AlphaFold2 models reveal a putative ion permeation pathway in TMC4 and 5, and molecular dynamics simulations predict both proteins can conduct ions and perform lipid scrambling. These findings raise the possibility that TMC4 and 5 interact with CIB3 at microvillar tips to form a mechanosensitive complex, akin to TMC1 and 2, and CIB2 and 3, within the mechanotransduction channel complex at the tips of inner ear stereocilia.\n                <\/jats:p>","DOI":"10.1101\/2024.08.22.609173","type":"posted-content","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T14:40:23Z","timestamp":1724424023000},"source":"Crossref","is-referenced-by-count":6,"title":["Transmembrane channel-like 4 and 5 proteins at microvillar tips are potential ion channels and lipid scramblases"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-2432","authenticated-orcid":false,"given":"Seham","family":"Ebrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5796-6875","authenticated-orcid":false,"given":"Angela","family":"Ballesteros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Sharon Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shounak","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaizun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hsiang","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan S.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaw","family":"Agyemang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runjia","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Krystofiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Sotomayor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bechara","family":"Kachar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024082722250419000_2024.08.22.609173v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.5"},{"key":"2024082722250419000_2024.08.22.609173v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9871"},{"key":"2024082722250419000_2024.08.22.609173v1.3","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E17-01-0021"},{"key":"2024082722250419000_2024.08.22.609173v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.225"},{"key":"2024082722250419000_2024.08.22.609173v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21224"},{"key":"2024082722250419000_2024.08.22.609173v1.6","doi-asserted-by":"crossref","unstructured":"Burman, A. et al. 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