4IQH

Alternate Splicing of Dysferlin C2A Confers Ca(2+)-Dependent and Ca(2+)-Independent Binding for Membrane Repair.

(2014) Structure 22: 104-115

• PubMed: 24239457 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1016/j.str.2013.10.001
• Primary Citation of Related Structures:  
  4IHB, 4IQH


• PubMed Abstract: 
  

  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 "canonical" 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.

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Organizational Affiliation: 

Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.