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bioRxiv · 10.1101/2020.11.13.381293

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

Nguyen, G. T. T.·Sutinen, A.·Raasakka, A.·Muruganandam, G.·Loris, R.·Kursula, P.
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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.

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Nguyen, G. T. T., Sutinen, A., Raasakka, A., Muruganandam, G., Loris, R., Kursula, P.. 2020-11-14. Structure of the complete dimeric human GDAP1 core domain provides insights into ligand binding and clustering of disease mutations. https://doi.org/10.1101/2020.11.13.381293

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