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Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy

Author

Listed:
  • Naoyuki Kuwabara

    (High Energy Accelerator Research Organization)

  • Rieko Imae

    (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku)

  • Hiroshi Manya

    (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku)

  • Tomohiro Tanaka

    (The Noguchi Institute, Itabashi-ku)

  • Mamoru Mizuno

    (The Noguchi Institute, Itabashi-ku)

  • Hiroki Tsumoto

    (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku)

  • Motoi Kanagawa

    (Kobe University Graduate School of Medicine)

  • Kazuhiro Kobayashi

    (Kobe University Graduate School of Medicine)

  • Tatsushi Toda

    (Kobe University Graduate School of Medicine
    The University of Tokyo)

  • Toshiya Senda

    (High Energy Accelerator Research Organization
    School of High Energy Accelerator Science, SOKENDAI)

  • Tamao Endo

    (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku)

  • Ryuichi Kato

    (High Energy Accelerator Research Organization
    School of High Energy Accelerator Science, SOKENDAI)

Abstract

α-Dystroglycan (α-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of α-DG cause dystroglycanopathy, a group of congenital muscular dystrophies. The core M3 O-mannosyl glycan contains tandem ribitol-phosphate (RboP), a characteristic feature first found in mammals. Fukutin and fukutin-related protein (FKRP), whose mutated genes underlie dystroglycanopathy, sequentially transfer RboP from cytidine diphosphate-ribitol (CDP-Rbo) to form a tandem RboP unit in the core M3 glycan. Here, we report a series of crystal structures of FKRP with and without donor (CDP-Rbo) and/or acceptor [RboP-(phospho-)core M3 peptide] substrates. FKRP has N-terminal stem and C-terminal catalytic domains, and forms a tetramer both in crystal and in solution. In the acceptor complex, the phosphate group of RboP is recognized by the catalytic domain of one subunit, and a phosphate group on O-mannose is recognized by the stem domain of another subunit. Structure-based functional studies confirmed that the dimeric structure is essential for FKRP enzymatic activity.

Suggested Citation

  • Naoyuki Kuwabara & Rieko Imae & Hiroshi Manya & Tomohiro Tanaka & Mamoru Mizuno & Hiroki Tsumoto & Motoi Kanagawa & Kazuhiro Kobayashi & Tatsushi Toda & Toshiya Senda & Tamao Endo & Ryuichi Kato, 2020. "Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14220-z
    DOI: 10.1038/s41467-019-14220-z
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