{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T02:46:59Z","timestamp":1778813219993,"version":"3.51.4"},"reference-count":72,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 DC000156"],"award-info":[{"award-number":["R01 DC000156"]}]},{"name":"NIH","award":["P30 CA022453"],"award-info":[{"award-number":["P30 CA022453"]}]},{"name":"NIH","award":["R50 CA251068"],"award-info":[{"award-number":["R50 CA251068"]}]},{"name":"Jain Foundation","award":["R01 DC000156"],"award-info":[{"award-number":["R01 DC000156"]}]},{"name":"Jain Foundation","award":["P30 CA022453"],"award-info":[{"award-number":["P30 CA022453"]}]},{"name":"Jain Foundation","award":["R50 CA251068"],"award-info":[{"award-number":["R50 CA251068"]}]},{"name":"Wayne State University Research Funds","award":["R01 DC000156"],"award-info":[{"award-number":["R01 DC000156"]}]},{"name":"Wayne State University Research Funds","award":["P30 CA022453"],"award-info":[{"award-number":["P30 CA022453"]}]},{"name":"Wayne State University Research Funds","award":["R50 CA251068"],"award-info":[{"award-number":["R50 CA251068"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Quantitative surface plasmon resonance (SPR) was utilized to determine binding strength and calcium dependence of direct interactions between dysferlin and proteins likely to mediate skeletal muscle repair, interrupted in limb girdle muscular dystrophy type 2B\/R2. Dysferlin canonical C2A (cC2A) and C2F\/G domains directly interacted with annexin A1, calpain-3, caveolin-3, affixin, AHNAK1, syntaxin-4, and mitsugumin-53, with cC2A the primary target and C2F lesser involved, overall demonstrating positive calcium dependence. Dysferlin C2 pairings alone showed negative calcium dependence in almost all cases. Like otoferlin, dysferlin directly interacted via its carboxy terminus with FKBP8, an anti-apoptotic outer mitochondrial membrane protein, and via its C2DE domain with apoptosis-linked gene (ALG-2\/PDCD6), linking anti-apoptosis with apoptosis. Confocal Z-stack immunofluorescence confirmed co-compartmentalization of PDCD6 and FKBP8 at the sarcolemmal membrane. Our evidence supports the hypothesis that prior to injury, dysferlin C2 domains self-interact and give rise to a folded, compact structure as indicated for otoferlin. With elevation of intracellular Ca2+ in injury, dysferlin would unfold and expose the cC2A domain for interaction with annexin A1, calpain-3, mitsugumin 53, affixin, and caveolin-3, and dysferlin would realign from its interactions with PDCD6 at basal calcium levels to interact strongly with FKBP8, an intramolecular rearrangement facilitating membrane repair.<\/jats:p>","DOI":"10.3390\/ijms24054707","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T02:28:17Z","timestamp":1677637697000},"page":"4707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca2+ Elevation via PDCD6 and FKBP8"],"prefix":"10.3390","volume":"24","author":[{"given":"Dennis G.","family":"Drescher","sequence":"first","affiliation":[{"name":"Laboratory of Bio-otology, Department of Otolaryngology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian J.","family":"Drescher","sequence":"additional","affiliation":[{"name":"Laboratory of Bio-otology, Department of Otolaryngology, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dakshnamurthy","family":"Selvakumar","sequence":"additional","affiliation":[{"name":"Laboratory of Bio-otology, Department of Otolaryngology, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeraja P.","family":"Annam","sequence":"additional","affiliation":[{"name":"Laboratory of Bio-otology, Department of Otolaryngology, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.nmd.2018.05.007","article-title":"LGMD workshop study group. 229th ENMC international workshop: Limb girdle muscular dystrophies\u2014Nomenclature and reformed classification","volume":"28","author":"Straub","year":"2018","journal-title":"Neuromuscul. 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