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Review
. 2016 Oct;196(1):37-47.
doi: 10.1016/j.jsb.2016.06.015. Epub 2016 Jun 23.

Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2

Annika Hohendahl  1 , Aurélien Roux  2 , Valentina Galli  1
Affiliations
Review

Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2

Annika Hohendahl et al. J Struct Biol. 2016 Oct.

Abstract

Centronuclear myopathies (CNMs) are genetic diseases whose symptoms are muscle weakness and atrophy (wasting) and centralised nuclei. Recent human genetic studies have isolated several groups of mutations. Among them, many are found in two interacting proteins essential to clathrin-mediated endocytosis, dynamin and the BIN-Amphiphysin-Rvs (BAR) protein BIN1/amphiphysin 2. In this review, by using structural and functional data from the study of endocytosis mainly, we discuss how the CNM mutations could affect the structure and the function of these ubiquitous proteins and cause the muscle-specific phenotype. The literature shows that both proteins are involved in the plasma membrane tubulation required for T-tubule biogenesis. However, this system also requires the regulation of the dynamin-mediated membrane fission, and the formation of a stable protein-scaffold to maintain the T-tubule structure. We discuss how the specific functions, isoforms and partners (myotubularin in particular) of these two proteins can lead to the establishment of muscle-specific features.

Keywords: BAR domain; BIN1; Centranuclear myopathy; Clathrin-mediated endocytosis; Dynamin; Membrane fission; Muscle; Myotubularin; Structure; T-tubule.

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Figures

Fig. 1
Fig. 1
BIN1 and dynamin 2 domain structure. BIN1, upper panel. Dynamin 2, lower panel. Arrowheads indicate positions of CNM-linked mutations. For BIN1, isoform numbers are indicated on the left, the tissues in which the isoforms are expressed on the right. Semi-transparency of exons indicates alternative splicing within the different isoforms in this tissue.
Fig. 2
Fig. 2
Structural consequences of CNM-linked mutations in BIN1. A. Helical wheel projection of residues 18-36 (amphipathic helix) from human BIN1 and likely new positioning due to ΔK21, R24C and K35N. B. Affected residues of truncation of SH3 domain. Lacking parts in human K575X mutant in violet; human F588 (blue) is part of dynamin binding face (green); crystal structure from rat BIN1 (Owen et al., 1998). Charged residues are marked in violet (positive) and blue (negative), hydrophobic residues in green and polar uncharged residues in grey. C, D. D151 and R154 are on the tip of the BIN1 BAR domain dimer and point sideways. Visualisation of a BAR domain dimer from the front, with each monomer in a different grey shade (C). Side view (D).
Fig. 3
Fig. 3
Dynamin tetramer structure. Structure of the dynamin tetramer (Reubold et al., 2015) with represented dynamin 2 CNM-related mutations. The inlets show the interface between the stalk and the PH domain (right panel) and mutation R465 W (left panel).
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