Dystrophin is a microtubule-associated protein

Abstract

Cytolinkers are giant proteins that can stabilize cells by linking actin filaments, intermediate filaments, and microtubules (MTs) to transmembrane complexes. Dystrophin is functionally similar to cytolinkers, as it links the multiple components of the cellular cytoskeleton to the transmembrane dystroglycan complex. Although no direct link between dystrophin and MTs has been documented, costamere-associated MTs are disrupted when dystrophin is absent. Using tissue-based cosedimentation assays on mice expressing endogenous dystrophin or truncated transgene products, we find that constructs harboring spectrinlike repeat 24 through the first third of the WW domain cosediment with MTs. Purified Dp260, a truncated isoform of dystrophin, bound MTs with a Kd of 0.66 µM, a stoichiometry of 1 Dp260/1.4 tubulin heterodimer at saturation, and stabilizes MTs from cold-induced depolymerization. Finally, α- and β-tubulin expression is increased ∼2.5-fold in mdx skeletal muscle without altering the tubulin–MT equilibrium. Collectively, these data suggest dystrophin directly organizes and/or stabilizes costameric MTs and classifies dystrophin as a cytolinker in skeletal muscle.

Microtubule binding distinguishes dystrophin from utrophin

“…Although the mdx mouse expresses increased utrophin, these levels fail to restore nNOS to the sarcolemma or rescue the disorganized microtubule lattice that results owing to loss of dystrophin (16,19,34,35), indicating that utrophin cannot fully compensate for the lack of dystrophin. There are two main possibilities why endogenously up-regulated utrophin fails to retain microtubule lattice organization.…”

“…Through its many protein interactions, dystrophin is hypothesized to protect against contraction-induced muscle damage via radial force transmission and stabilization of the sarcolemma (13)(14)(15). Additionally, through both direct and indirect interactions via proteins such as ankyrin-B and obscurin, dystrophin has been found to bind microtubules to form a rectilinear lattice beneath the sarcolemma (16)(17)(18)(19)(20).…”

eDystrophin : un nouvel outil dédié à une meilleure compréhension des dystrophinopathies

“…Leur connaissance est essentielle pour élucider la fonctionnalité de la dystrophine normale et de ses variants pathologiques. Le domaine central en particulier possède de multiples interactions avec les lipides membranaires qui maintiennent la dystrophine en contact avec le sarcolemme [17,18], l'actine [2], la sérine/thréonine kinase Par-1b [39], les filaments intermédiaires de type synémines α et β [4], les microtubules [29] et une protéine enzymatique jouant un rôle clé dans l'activité musculaire, l'oxyde nitrique synthase neuronale ou nNOS [15,20]. Les premières mutations du gène DMD ont été identifiées il y a 30 ans.…”

“…La dystrophine est composée de quatre grands domaines [14,16] (Figure 1 [17,18], l'actine (domaine ABD2, répétitions 11-17) [2], la sérine/thréonine kinase Par-1b (répétitions R8-R9) [39], les synémines α et β qui sont des protéines de la famille des filaments intermédiaires (répétitions R11-R14) [4] et l'oxyde nitrique synthétase neuronale ou nNOS (répétitions R16-R17) [15,20] et enfin les microtubules (répétitions R20-24) [29] permettant de maintenir près du sarcolemme cette protéine enzymatique jouant un rôle clé dans l'activité musculaire.…”

“…Le domaine CRR se lie avec le β-dystroglycane (β-DG) qui, en interagissant avec l'α-dystroglycane et les sarcoglycanes, forme le complexe dystrophine-glycoprotéines (DGC) [5,9]. Il se lie aussi à la syné-mine α [4], la plectine [31], la myosprine (protéine kinase de type A) [29] et l'ankyrine [3].…”