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

DOI: 10.3389/fmolb.2020.631232 DOI Help

Authors: Giang Thi Tuyet Nguyen (University of Oulu; University of Bergen) , Aleksi Sutinen (University of Oulu; University of Bergen) , Arne Raasakka (VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie) , Gopinath Muruganandam (VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie; Vrije Universiteit Brussel) , Remy Loris (VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie; Vrije Universiteit Brussel) , Petri Kursula (University of Oulu; University of Bergen)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Frontiers In Molecular Biosciences , VOL 7

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 19951

Open Access Open Access

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.

Journal Keywords: protein structure; ganglioside-induced differentiation-associated protein 1; Charcot-Marie-Tooth disease; oligomeric state; fatty acid; membrane protein

Diamond Keywords: Charcot-Marie-Tooth disease (CMT)

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: B21-High Throughput SAXS , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: P11 and P12 at DESY/EMBL; SWING beamline at SOLEIL

Added On: 24/02/2021 08:34


Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)