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

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....

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Giang Thi Tuyet Nguyen, Sutinen, Aleksi, Raasakka, Arne, Muruganandam, Gopinath, Remy Loris, Kursula, Petri
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.11.2020
Subjects
Allosteric properties
Calcium (mitochondrial)
Calcium homeostasis
Calcium permeability
Charcot-Marie-Tooth disease
Crystal structure
Dimerization
Fatty acids
Glutathione transferase
Homeostasis
Ligands
Membrane permeability
Mitochondria
Neurological diseases
Oligomerization
Protein structure
Proteins
Structure-function relationships
Online AccessGet full text

Cover

More Information
Summary: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 towards 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 towards allosteric mechanisms in regulating GDAP1 oligomeric state and function. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.11.13.381293