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

Onderzoeksoutput: Articlepeer review

5 Citaten (Scopus)
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Samenvatting

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.
Originele taal-2English
Artikelnummer631232
Pagina's (van-tot)1-18
Aantal pagina's18
TijdschriftFrontiers in Molecular Biosciences
Volume7
DOI's
StatusPublished - 27 jan 2021

Bibliografische nota

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

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