University of Oulu

Nguyen GTT, Sutinen A, Raasakka A, Muruganandam G, Loris R and Kursula P (2021) Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations. Front. Mol. Biosci. 7:631232. doi: 10.3389/fmolb.2020.631232

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

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Author: Nguyen, Giang Thi Tuyet1,2; Sutinen, Aleksi1,2; Raasakka, Arne3;
Organizations: 1Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
2Department of Biomedicine, University of Bergen, Bergen, Norway
3VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
4Department of Bioengineering Sciences, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.4 MB)
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Language: English
Published: Frontiers Media, 2021
Publish Date: 2021-04-30


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.

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Series: Frontiers in molecular biosciences
ISSN: 2296-889X
ISSN-E: 2296-889X
ISSN-L: 2296-889X
Volume: 7
Article number: 631232
DOI: 10.3389/fmolb.2020.631232
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was funded by the Academy of Finland, project number 24302881. The research leading to this result has been supported by the project CALIPSOplus under the Grant Agreement 730872, as well as by iNEXT, grant number 653706, from the EU Framework Program for Research and Innovation HORIZON 2020.
EU Grant Number: (653706) iNEXT - Infrastructure for NMR, EM and X-rays for translational research
Copyright information: © 2021 Nguyen, Sutinen, Raasakka, Muruganandam, Loris and Kursula. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.