論文

査読有り 国際誌
2020年11月13日

Mutant BIN1-Dynamin 2 complexes dysregulate membrane remodeling in the pathogenesis of centronuclear myopathy.

The Journal of biological chemistry
  • Kenshiro Fujise
  • ,
  • Mariko Okubo
  • ,
  • Tadashi Abe
  • ,
  • Hiroshi Yamada
  • ,
  • Ichizo Nishino
  • ,
  • Satoru Noguchi
  • ,
  • Kohji Takei
  • ,
  • Tetsuya Takeda

記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1074/jbc.RA120.015184

Membrane remodeling is required for dynamic cellular processes such as cell division, polarization and motility. BAR domain proteins and dynamins are key molecules in membrane remodeling that work together for membrane deformation and fission. In striated muscles, sarcolemmal invaginations termed T-tubules are required for excitation-contraction coupling. BIN1 and DNM2, which encode a BAR domain protein BIN1 and dynamin 2, respectively, have been reported to be causative genes of centronuclear myopathy (CNM), a hereditary degenerative disease of skeletal muscle, and deformation of T-tubules is often observed in the CNM patients. However, it remains unclear how BIN1 and dynamin 2 are implicated in T-tubule biogenesis, and how mutations in these molecules cause CNM to develop.Here, using an in cellulo reconstitution assay, we demonstrate that dynamin 2 is required for stabilization of membranous structures equivalent to T-tubules. GTPase activity of wild type dynamin 2 is suppressed through interaction with BIN1, whereas that of the disease-associated mutant dynamin 2 remains active due to lack of the BIN1-mediated regulation thus causing aberrant membrane remodeling. Finally, we show that in cellulo aberrant membrane remodeling by mutant dynamin 2 variants is correlated with their enhanced membrane fission activities, and the results can explain severity of the symptoms in patients. Thus, this study provides molecular insights into dysregulated membrane remodeling triggering the pathogenesis of DNM2-related centronuclear myopathy.

リンク情報
DOI
https://doi.org/10.1074/jbc.RA120.015184
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33187981
ID情報
  • DOI : 10.1074/jbc.RA120.015184
  • PubMed ID : 33187981

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