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AHNAK, a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration

Lookup NU author(s): Dr Steven Laval, Dr Louise VB Anderson, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby

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Abstract

Mutations in dysferlin cause limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. Dysferlin is proposed to play a role in muscle membrane repair. To gain functional insight into the molecular mechanisms of dysferlin, we have searched for dysferlin-interacting proteins in skeletal muscle. By coimmunoprecipitation coupled with mass spectrometry, we demonstrate that AHNAK interacts with dysferlin. We defined the binding sites in dysferlin and AHNAK as the C2A domain in dysferlin and the carboxyterminal domain of AHNAK by glutathione S-transferase (GST)-pull down assays. As expected, the N-terminal domain of myoferlin also interacts with the carboxyterminal domain of AHNAK. In normal skeletal muscle, dysferlin and AHNAK colocalize at the sarcolemmal membrane and T-tubules. In dysferlinopathies, reduction or absence of dysferlin correlates with a secondary muscle-specific loss of AHNAK. Moreover, in regenerating rat muscle, dysferlin and AHNAK showed a marked increase and cytoplasmic localization, consistent with the direct interaction between them. Our data suggest that dysferlin participates in the recruitment and stabilization of AHNAK to the sarcolemma and that AHNAK plays a role in dysferlin membrane repair process. It may also have significant implications for understanding the biology of AHNAK-containing exocytotic vesicles, "enlargosomes," in plasma membrane remodeling and repair. © FASEB.


Publication metadata

Author(s): Huang Y, Laval SH, Van Remoortere A, Baudier J, Benaud C, Anderson LVB, Straub V, Deelder A, Frants RR, Den Dunnen JT, Bushby K, Van Der Maarel SM

Publication type: Article

Publication status: Published

Journal: FASEB Journal

Year: 2007

Volume: 21

Issue: 3

Pages: 732-742

Print publication date: 01/03/2007

ISSN (print): 0892-6638

ISSN (electronic): 1530-6860

Publisher: Federation of American Societies for Experimental Biology

URL: http://dx.doi.org/10.1096/fj.06-6628com

DOI: 10.1096/fj.06-6628com

PubMed id: 17185750


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Funding

Funder referenceFunder name
R21-AR48327-01NIAMS NIH HHS

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