Format

Send to

Choose Destination
Structure. 2014 Jan 7;22(1):104-15. doi: 10.1016/j.str.2013.10.001. Epub 2013 Nov 14.

Alternate splicing of dysferlin C2A confers Ca²⁺-dependent and Ca²⁺-independent binding for membrane repair.

Author information

1
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.
2
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth 55812 MN, USA.
3
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
4
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. Electronic address: roger.b.sutton@ttuhsc.edu.

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.

PMID:
24239457
PMCID:
PMC5993433
DOI:
10.1016/j.str.2013.10.001
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center