Alternate Splicing of Dysferlin C2A Confers Ca²⁺-Dependent and Ca²⁺-Independent Binding for Membrane Repair

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• 作者：Kerry Fuson ; Anne Rice ; Ryan Mahling ; Adam Snow ; Kamakshi Nayak ; Prajna Shanbhogue ; Austin聽G. Meyer ; Gregory M.I. Redpath ; Anne Hinderliter ; S ; ra聽T. Cooper ; R.聽Bryan Sutton
• 刊名：Structure
• 出版年：7 January, 2014
• 年：2014
• 卷：22
• 期：1
• 页码：104-115
• 全文大小：3217 K

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Summary

Dysferlin plays a critical role in the Ca²⁺-dependent repair of microlesions that occur in the muscle sarcolemma. Of the seven C2 domains in dysferlin, only C2A is reported to bind both Ca²⁺ and phospholipid, thus acting as a key sensor in membrane repair. Dysferlin C2A exists as two isoforms, the 鈥渃anonical鈥?C2A and C2A variant 1 (C2Av1). Interestingly, these isoforms have markedly different responses to Ca²⁺ and phospholipid. Structural and thermodynamic analyses are consistent with the canonical C2A domain as a Ca²⁺-dependent, phospholipid-binding domain, whereas C2Av1 would likely be Ca²⁺-independent under physiological conditions. Additionally, both isoforms display remarkably low free energies of stability, indicative of a highly flexible structure. The inverted ligand preference and flexibility for both C2A isoforms suggest the capability for both constitutive and Ca²⁺-regulated effector interactions, an activity that would be essential in its role as a mediator of membrane repair.