Proteomic Analysis of the Dysferlin Protein Complex Unveils Its Importance for Sarcolemmal Maintenance and Integrity

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Nov 17

PMID 21079765

Citations 38

Authors

Antoine de Morree

Paul J Hensbergen

Herman H H B M van Haagen

Irina Dragan

Andre M Deelder

Peter A C t Hoen

Rune R Frants

Silvere M van der Maarel

Affiliations

Soon will be listed here.

Abstract

Dysferlin is critical for repair of muscle membranes after damage. Mutations in dysferlin lead to a progressive muscular dystrophy. Recent studies suggest additional roles for dysferlin. We set out to study dysferlin's protein-protein interactions to obtain comprehensive knowledge of dysferlin functionalities in a myogenic context. We developed a robust and reproducible method to isolate dysferlin protein complexes from cells and tissue. We analyzed the composition of these complexes in cultured myoblasts, myotubes and skeletal muscle tissue by mass spectrometry and subsequently inferred potential protein functions through bioinformatics analyses. Our data confirm previously reported interactions and support a function for dysferlin as a vesicle trafficking protein. In addition novel potential functionalities were uncovered, including phagocytosis and focal adhesion. Our data reveal that the dysferlin protein complex has a dynamic composition as a function of myogenic differentiation. We provide additional experimental evidence and show dysferlin localization to, and interaction with the focal adhesion protein vinculin at the sarcolemma. Finally, our studies reveal evidence for cross-talk between dysferlin and its protein family member myoferlin. Together our analyses show that dysferlin is not only a membrane repair protein but also important for muscle membrane maintenance and integrity.

Citing Articles

Cryo-EM structures of the membrane repair protein dysferlin.

Huang H, Grandinetti G, Heissler S, Chinthalapudi K Nat Commun. 2024; 15(1):9650.

PMID: 39511170 PMC: 11544258. DOI: 10.1038/s41467-024-53773-6.

Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy.

Khodabukus A, Prabhu N, Roberts T, Buldo M, Detwiler A, Fralish Z Adv Sci (Weinh). 2024; 11(31):e2400188.

PMID: 38887849 PMC: 11336985. DOI: 10.1002/advs.202400188.

Otoferlin as a multirole Ca signaling protein: from inner ear synapses to cancer pathways.

Leclere J, Dulon D Front Cell Neurosci. 2023; 17:1197611.

PMID: 37538852 PMC: 10394277. DOI: 10.3389/fncel.2023.1197611.

Tetraspanin CD82 Associates with Trafficking Vesicle in Muscle Cells and Binds to Dysferlin and Myoferlin.

Fontelonga T, Hall A, Brown J, Jung Y, Alexander M, Dominov J Adv Biol (Weinh). 2023; 7(12):e2300157.

PMID: 37434585 PMC: 10784410. DOI: 10.1002/adbi.202300157.

Role of calcium-sensor proteins in cell membrane repair.

Li Z, Shaw G Biosci Rep. 2023; 43(2).

PMID: 36728029 PMC: 9970828. DOI: 10.1042/BSR20220765.

References

Lennon N, Kho A, Bacskai B, Perlmutter S, Hyman B, Brown Jr R . Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem. 2003; 278(50):50466-73. DOI: 10.1074/jbc.M307247200. View

Hernandez-Deviez D, Howes M, Laval S, Bushby K, Hancock J, Parton R . Caveolin regulates endocytosis of the muscle repair protein, dysferlin. J Biol Chem. 2007; 283(10):6476-88. DOI: 10.1074/jbc.M708776200. View

Borgonovo B, Cocucci E, Racchetti G, Podini P, Bachi A, Meldolesi J . Regulated exocytosis: a novel, widely expressed system. Nat Cell Biol. 2002; 4(12):955-62. DOI: 10.1038/ncb888. View

Matsuda C, Kameyama K, Suzuki A, Mishima W, Yamaji S, Okamoto H . Affixin activates Rac1 via betaPIX in C2C12 myoblast. FEBS Lett. 2008; 582(8):1189-96. DOI: 10.1016/j.febslet.2008.01.064. View

Patel P, Harris R, Geddes S, Strehle E, Watson J, Bashir R . Solution structure of the inner DysF domain of myoferlin and implications for limb girdle muscular dystrophy type 2b. J Mol Biol. 2008; 379(5):981-90. DOI: 10.1016/j.jmb.2008.04.046. View

de Luna N, Freixas A, Gallano P, Caselles L, Rojas-Garcia R, Paradas C . Dysferlin expression in monocytes: a source of mRNA for mutation analysis. Neuromuscul Disord. 2006; 17(1):69-76. DOI: 10.1016/j.nmd.2006.09.006. View

Roux I, Safieddine S, Nouvian R, Grati M, Simmler M, Bahloul A . Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell. 2006; 127(2):277-89. DOI: 10.1016/j.cell.2006.08.040. View

Ampong B, Imamura M, Matsumiya T, Yoshida M, Takeda S . Intracellular localization of dysferlin and its association with the dihydropyridine receptor. Acta Myol. 2006; 24(2):134-44. View

Hayashi Y, Chou F, Engvall E, Ogawa M, Matsuda C, Hirabayashi S . Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet. 1998; 19(1):94-7. DOI: 10.1038/ng0598-94. View

10.

Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C . Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet. 2007; 16(6):618-29. DOI: 10.1093/hmg/ddm002. View

11.

Krajacic P, Hermanowski J, Lozynska O, Khurana T, Lamitina T . C. elegans dysferlin homolog fer-1 is expressed in muscle, and fer-1 mutations initiate altered gene expression of muscle enriched genes. Physiol Genomics. 2009; 40(1):8-14. PMC: 2807209. DOI: 10.1152/physiolgenomics.00106.2009. View

12.

Luft F . Dysferlin, dystrophy, and dilatative cardiomyopathy. J Mol Med (Berl). 2007; 85(11):1157-9. DOI: 10.1007/s00109-007-0252-8. View

13.

Mellgren R, Miyake K, Kramerova I, Spencer M, Bourg N, Bartoli M . Calcium-dependent plasma membrane repair requires m- or mu-calpain, but not calpain-3, the proteasome, or caspases. Biochim Biophys Acta. 2009; 1793(12):1886-93. PMC: 2787696. DOI: 10.1016/j.bbamcr.2009.09.013. View

14.

Azakir B, Di Fulvio S, Therrien C, Sinnreich M . Dysferlin interacts with tubulin and microtubules in mouse skeletal muscle. PLoS One. 2010; 5(4):e10122. PMC: 2853571. DOI: 10.1371/journal.pone.0010122. View

15.

Rutgers K, van Remoortere A, van Buchem M, Verrips C, Greenberg S, Bacskai B . Differential recognition of vascular and parenchymal beta amyloid deposition. Neurobiol Aging. 2009; 32(10):1774-83. PMC: 2891162. DOI: 10.1016/j.neurobiolaging.2009.11.012. View

16.

De Luna N, Gallardo E, Sonnet C, Chazaud B, Dominguez-Perles R, Suarez-Calvet X . Role of thrombospondin 1 in macrophage inflammation in dysferlin myopathy. J Neuropathol Exp Neurol. 2010; 69(6):643-53. DOI: 10.1097/NEN.0b013e3181e0d01c. View

17.

Klinge L, Laval S, Keers S, Haldane F, Straub V, Barresi R . From T-tubule to sarcolemma: damage-induced dysferlin translocation in early myogenesis. FASEB J. 2007; 21(8):1768-76. DOI: 10.1096/fj.06-7659com. View

18.

Disatnik M, Rando T . Integrin-mediated muscle cell spreading. The role of protein kinase c in outside-in and inside-out signaling and evidence of integrin cross-talk. J Biol Chem. 1999; 274(45):32486-92. DOI: 10.1074/jbc.274.45.32486. View

19.

Martinez L, Jacquet S, Esteve J, Rolland C, Cabezon E, Champagne E . Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature. 2003; 421(6918):75-9. DOI: 10.1038/nature01250. View

20.

Therrien C, Di Fulvio S, Pickles S, Sinnreich M . Characterization of lipid binding specificities of dysferlin C2 domains reveals novel interactions with phosphoinositides. Biochemistry. 2009; 48(11):2377-84. DOI: 10.1021/bi802242r. View