Structure of the complete dimeric human GDAP1 core domain provides insights into ligand binding and clustering of disease mutations

Giang Thi Tuyet Nguyen, Aleksi Sutinen, Arne Raasakka, Gopinath Muruganandam, Remy Loris, Petri Kursula

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Despite the common involvement of ganglioside-induced differentiation-associated protein 1 (GDAP1) in CMT, the protein structure and function, as well as the pathogenic mechanisms, remain unclear. We determined the crystal structure of the complete human GDAP1 core domain, which shows a novel mode of dimerization within the glutathione S-transferase (GST) family. The long GDAP1-specific insertion forms an extended helix and a flexible loop. GDAP1 is catalytically inactive toward classical GST substrates. Through metabolite screening, we identified a ligand for GDAP1, the fatty acid hexadecanedioic acid, which is relevant for mitochondrial membrane permeability and Ca2+ homeostasis. The fatty acid binds to a pocket next to a CMT-linked residue cluster, increases protein stability, and induces changes in protein conformation and oligomerization. The closest homologue of GDAP1, GDAP1L1, is monomeric in its full-length form. Our results highlight the uniqueness of GDAP1 within the GST family and point toward allosteric mechanisms in regulating GDAP1 oligomeric state and function.
Original languageEnglish
Article number631232
Pages (from-to)1-18
Number of pages18
JournalFrontiers in Molecular Biosciences
Volume7
DOIs
Publication statusPublished - 27 Jan 2021

Bibliographical note

Copyright © 2021 Nguyen, Sutinen, Raasakka, Muruganandam, Loris and Kursula.

Keywords

  • protein structure
  • ganglioside-induced differentiation-associated protein 1
  • Charcot-Marie-Tooth disease
  • oligomeric state
  • fatty acid
  • membrane protein

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