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Dysferlin is a \u223c230-kDa protein comprised of multiple C2 domains, Fer and Dysf domains, and a transmembrane domain that anchors it to the transverse tubule membrane at the triad junction (TJ). Here we show that replacing C2A with other C2 domains yields fusion proteins that are less active in supporting Ca2+ signaling than WT dysferlin. We also show that the most N-terminal of dysferlin\u2019s C2 domains, C2A (DysfC2A), is sufficient to support normal Ca2+ signaling and sarcolemmal repair in dysferlin-null muscle, though it accumulates at TJs inefficiently. The C2A domains of myoferlin and PKC\u03b1, though homologous, are less active. The C2 domain of PKC\u03b1 (PKC\u03b1C2) targets the TJ more efficiently than DysfC2A, however. Fusion proteins containing one or two PKC\u03b1C2 domains accumulate at the TJ and are active in sarcolemmal membrane repair, but they do not support normal Ca2+ signaling unless linked to DysfC2A Control of Ca2+ signaling is fully restored when the PKC\u03b1C2 domain, alone or in pairs, is linked to DysfC2A. This suggests that the DysfC2A is sufficient to support two major functions of dysferlin in skeletal muscle, and that its effect on Ca2+ signaling is specific. We propose that the PKC\u03b1C2\u2013PKC\u03b1C2-DysfC2A fusion protein is a promising candidate for future viral gene therapy treatment for dysferlinopathy.<\/jats:p>","DOI":"10.1085\/jgp.202513844","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:20:48Z","timestamp":1773901248000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Dysferlin\u2019s C2A domain supports normal Ca2+ signaling and membrane repair in dysferlin-null myofibers"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-4603","authenticated-orcid":true,"given":"Valeriy","family":"Lukyanenko","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology and Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2878-6401","authenticated-orcid":true,"given":"Joaquin","family":"Muriel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology and Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8191-6310","authenticated-orcid":true,"given":"Kassidy K.","family":"Banford","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ohio State University 2 Department of Physiology and Cell Biology, , Columbus, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2280-5866","authenticated-orcid":true,"given":"Thomas A.","family":"Kwiatkowski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ohio State University 2 Department of Physiology and Cell Biology, , Columbus, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9020-5792","authenticated-orcid":true,"given":"Hannah R.","family":"Bulgart","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ohio State University 2 Department of Physiology and Cell Biology, , Columbus, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2710-3088","authenticated-orcid":true,"given":"Noah","family":"Weisleder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rs6vg23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ohio State University 2 Department of Physiology and Cell Biology, , Columbus, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4933-3469","authenticated-orcid":true,"given":"Robert J.","family":"Bloch","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rq5mt64","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology and Physiology, , Baltimore, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026060409111288000_bib1","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.bpj.2013.11.4492","article-title":"Quantitation of the calcium and membrane binding properties of the C2 domains of dysferlin","volume":"106","author":"Abdullah","year":"2014","journal-title":"Biophys. 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