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 language | English |
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Article number | 631232 |
Pages (from-to) | 1-18 |
Number of pages | 18 |
Journal | Frontiers in Molecular Biosciences |
Volume | 7 |
DOIs | |
Publication status | Published - 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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Dimeric human ganglioside-induced differentiation-associated protein 1, construct GDAP1∆303-358
Loris, R. (Supervisor) & Muruganandam, G. (Creator), Small Angle Scattering Biological Data Bank, 2021
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