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Mutations in the human DP1 gene REEP1 are associated with Hereditary Spastic Paraplegia type 31 and distal hereditary motor neuropathy. Four missense mutations map to a putative dimerization interface but the impact of these mutations on DP1 structure and tubule formation are unknown. Combining biophysical measurements, functional assays, and computational modeling in the context of the model protein Yop1, we found that missense mutations have variable effects on DP1 dimer structure and in vitro tubulation activity, and provide mechanistic insights into the role of DP1 oligomerisation on membrane curvature stabilization. Whereas the mutations P71L and S75F decreased dimer homogeneity and led to polydisperse oligomerization and impaired membrane curving activity, A72E introduced new polar interactions between subunits that stabilized the Yop1 dimer and allowed robust tubule formation but prevented formation of more highly-curved lipoprotein particles (LPP). The introduction of a BRIL domain to the cytoplasmic loop of A72E rescued LPP formation, consistent with a requirement for dimer splaying in highly curved membranes. These results suggest that the membrane curving activity of DP1 proteins requires both dimer stability and conformational plasticity at the intermolecular interface.<\/jats:p>","DOI":"10.1042\/bcj20240190","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T15:17:20Z","timestamp":1727104640000},"page":"1437-1448","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Yop1 stability and membrane curvature generation propensity are controlled by its oligomerisation interface"],"prefix":"10.1042","volume":"481","author":[{"given":"Anu V.","family":"Chandran","sequence":"first","affiliation":[{"name":"1Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"2Department of Biology, University of Fribourg, Fribourg, Switzerland"},{"name":"3Departamento de Qu\u00edmica F\u00edsica y Anal\u00edtica, Universidad de Oviedo, Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Vanni","sequence":"additional","affiliation":[{"name":"2Department of Biology, University of Fribourg, Fribourg, Switzerland"},{"name":"4Swiss National Center for Competence in Research (NCCR) Bio-inspired Materials, University of Fribourg, Chemin des Verdiers 4, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8204-7608","authenticated-orcid":false,"given":"Jason R.","family":"Schnell","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"2024101113352879400_BCJ-2024-0190C1","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1096\/fj.02-1166hyp","article-title":"A reticular rhapsody: phylogenic evolution and nomenclature of the RTN\/Nogo gene family","volume":"17","year":"2003","journal-title":"FASEB J."},{"key":"2024101113352879400_BCJ-2024-0190C2","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.cell.2005.11.047","article-title":"A class of membrane proteins shaping the tubular endoplasmic reticulum","volume":"124","year":"2006","journal-title":"Cell"},{"key":"2024101113352879400_BCJ-2024-0190C3","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1146\/annurev.cellbio.042308.113324","article-title":"Mechanisms shaping the membranes of cellular organelles","volume":"25","year":"2009","journal-title":"Annu. 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