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It assembles ion channels, receptors and signaling molecules at synaptic and axonal membranes, particularly at the axon initial segment (AIS). However, the mechanism underlying the clustering of PSD93 at the AIS remains unclear. Here, we show that the secreted protein LGI1 and its transmembrane receptor ADAM22 are localized at the AIS of forebrain neurons. Using genetic knockout mice, we demonstrate that LGI1 and ADAM22 are reciprocally required for their clustering at the AIS, and the LGI1\u2013ADAM22 complex is required for the clustering of PSD93 at the AIS; ADAM22 recruits PSD93 to plasma membrane through its PDZ-binding motif. Together, these findings identify the LGI1\u2013ADAM22 complex as a key organizer of PSD93 clustering at the AIS.<\/jats:p>","DOI":"10.1242\/jcs.264880","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T08:17:51Z","timestamp":1783498671000},"source":"Crossref","is-referenced-by-count":0,"title":["The LGI1\u2013ADAM22 complex organizes PSD93 clustering at the axon initial segment"],"prefix":"10.1242","volume":"139","author":[{"given":"Wenying","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Life Sciences, Beijing Normal University 1 , Beijing 100875 ,","place":["China"]},{"name":"Guangdong Institute of Intelligence Science and Technology 2 , Hengqin, Zhuhai 519031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Tan","sequence":"additional","affiliation":[{"name":"Guangdong Institute of Intelligence Science and Technology 2 , Hengqin, Zhuhai 519031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yu","family":"Teng","sequence":"additional","affiliation":[{"name":"Guangdong Institute of Intelligence Science and Technology 2 , Hengqin, Zhuhai 519031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Hu","sequence":"additional","affiliation":[{"name":"Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital 3 Department of Prenatal Diagnosis, State Key Laboratory of Reproductive Medicine , , 210004 Nanjing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiejie","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Beijing Normal University 1 , Beijing 100875 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiong","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Institute of Intelligence Science and Technology 2 , Hengqin, Zhuhai 519031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-9818","authenticated-orcid":false,"given":"Yun Stone","family":"Shi","sequence":"additional","affiliation":[{"name":"Guangdong Institute of Intelligence Science and Technology 2 , Hengqin, Zhuhai 519031 ,","place":["China"]},{"name":"Model Animal Research Center, Medical School, Nanjing University 4 Ministry of Education Key Laboratory of Model Animal for Disease Study , , Nanjing 210032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026081206103469000_JCS264880C1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026081206103469000_JCS264880C2","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1007\/s00018-021-04088-y","article-title":"The LGI1 protein: molecular structure, physiological functions and disruption-related seizures","volume":"79","author":"Baudin","year":"2021","journal-title":"Cell. 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