7AIA

Complex of human GDAP1 with hexadecanedioic acid

This is a non-PDB format compatible entry.

Summary for 7AIA

• Entry DOI: 10.2210/pdb7aia/pdb
• Descriptor: Ganglioside-induced differentiation-associated protein 1, GLYCEROL, ETHANOL, ... (5 entities in total)
• Functional Keywords: homodimer, complex, mitochondria, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66664.26

Authors

Nguyen, G.T.T.,Sutinen, A.,Kursula, P. (deposition date: 2020-09-26, release date: 2021-02-24, Last modification date: 2024-11-20)

Primary citation

Nguyen, G.T.T.,Sutinen, A.,Raasakka, A.,Muruganandam, G.,Loris, R.,Kursula, P.
Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations.
Front Mol Biosci, 7:631232-631232, 2020

PubMed 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 Ca 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.

PubMed: 33585569
DOI: 10.3389/fmolb.2020.631232

Experimental method

X-RAY DIFFRACTION (2.2 Å)