{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:45:24Z","timestamp":1772160324617,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:p>\n                    In striated muscle, the regulatory complex of tropomyosin (Tpm) and troponin (Tn) governs the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010dependent interactions between myosin heads and actin, controlling muscle contraction. The N\u2010terminal and central regions of Tpm are crucial for Tn binding, yet their roles in regulating contraction in concert with Tn remain poorly understood. To explore this, we selected four pathogenic missense mutations in the\n                    <jats:italic>TPM2<\/jats:italic>\n                    gene encoding the skeletal Tpm2.2 isoform (\u03b2\u2010tropomyosin): D20H and E181K, associated with hypercontractility, and E41K and N202K, linked to hypocontractility. Using\n                    <jats:italic>in vitro<\/jats:italic>\n                    functional assays, we characterized these Tpm2.2 variants to unravel details of the molecular mechanisms underlying disease phenotypes. At low, non\u2010activating Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , all Tpm2.2 variants inhibited the Tn\u2010regulated steady\u2010state actomyosin ATPase reaction without affecting Tn binding to actin. At activating Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , hypocontractile mutants suppressed actomyosin ATPase activity and motor function more than wild\u2010type, suggesting interference with normal Tn regulation. Conversely, hypercontractile mutants enhanced myosin\u2010driven actin translocation. Arrhenius plots revealed a limited ability of E181K mutant to activate Tn\u2010regulated actomyosin ATPase at temperatures below 30\u2009\u00b0C, which was fully recovered, and even enhanced, at physiological temperatures. In the absence of actin, the N\u2010terminal mutations enhanced high\u2010affinity Tpm2.2\u2010Tn interactions, whereas central mutations had no effect. Additionally, although hypercontractile mutations increased Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010sensitivity of the cross\u2010bridge cycle, hypocontractile mutants decreased it. These findings demonstrate that mutations in the N\u2010terminal and central segments of Tpm2.2 disrupt Tn\u2010dependent regulation of actomyosin contractility through distinct mechanisms, providing new insights into the pathophysiology of Tpm\u2010related myopathies.\n                  <\/jats:p>","DOI":"10.1111\/febs.70180","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T12:34:19Z","timestamp":1752496459000},"page":"5789-5801","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Myopathy\u2010linked mutations in\n                    <i>TPM2<\/i>\n                    and their impact on troponin\u2010mediated regulation of actomyosin contractility"],"prefix":"10.1111","volume":"292","author":[{"given":"Recep","family":"K\u00fc\u00e7\u00fckdogru","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Faculty of Biological Sciences Kazimierz Wielki 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