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Numerous studies have established roles for titin in muscle function, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent interactions between titin and actin have been suggested to play a role in muscle contraction. The present study used co-sedimentation assays, dynamic force spectroscopy (DFS), and\n                    <jats:italic>in vitro<\/jats:italic>\n                    motility (IVM) assays to determine whether the N2A region of titin, overlooked in previous studies, interacts with actin in the presence of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . Co-sedimentation demonstrated that N2A \u2013 F-actin binding increases with increasing protein and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    concentration, DFS demonstrated increased rupture forces and decreased k\n                    <jats:sub>off<\/jats:sub>\n                    in the presence of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , and IVM demonstrated a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent reduction in motility of F-actin and reconstituted thin filaments in the presence of N2A. These results indicate that Ca\n                    <jats:sup>2+<\/jats:sup>\n                    increases the strength and stability of N2A \u2013 actin interactions, supporting the hypothesis that titin plays a regulatory role in muscle contraction. The results further support a model in which N2A \u2013 actin binding in active muscle increases titin stiffness, and that impairment of this mechanism contributes to the phenotype in muscular dystrophy with myositis. Future studies are required to determine whether titin \u2013 actin binding occurs in skeletal muscle sarcomeres\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-32952-8","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T06:27:46Z","timestamp":1537856866000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Calcium increases titin N2A binding to F-actin and regulated thin filaments"],"prefix":"10.1038","volume":"8","author":[{"given":"Samrat","family":"Dutta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Tsiros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Lavanyaa","family":"Sundar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humra","family":"Athar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Gage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiisa","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,1]]},"reference":[{"key":"32952_CR1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3233\/JND-160158","volume":"3","author":"M Savarese","year":"2016","unstructured":"Savarese, M., Sarparanta, J., Vihola, A., Udd, B. & Hackman, P. 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