Dysferlin Interacts with Annexins A1 and A2 and Mediates Sarcolemmal Wound-healing

Abstract

Mutations in the dysferlin gene cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy. We report here the results of expression profile analyses and in vitro investigations that point to an interaction between dysferlin and the Ca 2؉ and lipid-binding proteins, annexins A1 and A2, and define a role for dysferlin in Ca 2؉ -dependent repair of sarcolemmal injury through a process of vesicle fusion. Expression profiling identified a network of genes that are co-regulated in dysferlinopathic mice. Co-immunofluorescence, co-immunoprecipitation, and fluorescence lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and A2 in a Ca 2؉ and membrane injurydependent manner. The distribution of the annexins and the efficiency of sarcolemmal wound-healing are significantly disrupted in dysferlin-deficient muscle. We propose a model of muscle membrane healing mediated by dysferlin that is relevant to both normal and dystrophic muscle and defines the annexins as potential muscular dystrophy genes.

Distinctive patterns of microRNA expression in primary muscular disorders

“…Gene expression profiling of human and mouse normal and diseased skeletal muscle has generated more detailed insight in the molecular process underlying the different conditions (10)(11)(12)(13)(14). However, although each of these studies has identified a number of genes in various functional categories that are differentially expressed in the disease states, the substantial underlying disease mechanisms remain to be elucidated.…”

Structure of a C-terminal AHNAK peptide in a 1:2:2 complex with S100A10 and an acetylated N-terminal peptide of annexin A2

“…Depletion of AnxA2 by siRNA causes release of AHNAK into the cytoplasm, suggesting that (p11) 2 (AnxA2) 2 may recruit AHNAK to the plasma membrane and act as a scaffold, locating it nearby for cell membrane-repair activities and possibly regulation of membrane cyto-architecture (Benaud et al, 2004). Both AHNAK and annexins A1 and A2 have been shown to interact with dysferlin, a 230 kDa muscle membrane protein with roles in skeletal muscle regeneration and wound healing (Huang et al, 2007;Lennon et al, 2003;Cacciottolo et al, 2011). Furthermore, AHNAK-deficient mice were highly susceptible to Leishmania major infection owing to the proposed role of AHNAK in T-cell Ca 2+ signaling mediated by Ca v 1 channels based on loss-of-function experiments, the expression characteristics of AHNAK in T cells and the requirement of AHNAK for the expression of L-type calcium channels (Matza et al, 2008).…”

“…AHNAK, a large 629 kDa protein, has been implicated in membrane repair, and the annexin A2-S100A10 heterotetramer [(p11) 2 (AnxA2) 2 ] has high affinity for several regions of the long (1002-amino-acid) C-terminal domain of AHNAK (Shtivelman & Bishop, 1993;Benaud et al, 2004;Huang et al, 2007;Lennon et al, 2003;De Seranno et al, 2006;Rezvanpour et al, 2011).…”

Dysferlin stabilizes stress-induced Ca 2+ signaling in the transverse tubule membrane

“…These myopathies, most commonly limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), are independent of motor neuron activation (1), indicating that they are myogenic in origin. Dysferlin is a 230-kDa protein composed of seven C2 domains with homology to synaptotagmin (2,3) and a single transmembrane domain near its C terminus (4,5). The complexity of dysferlin's potential role in muscle is highlighted by the number of its purported functions, including membrane repair (2,3), vesicle fusion (4), microtubule regulation (5, 6), cell adhesion (7,8), and intercellular signaling (9).…”