dc.contributor.author | Nguyen, Giang Thi Tuyet | |
dc.contributor.author | Sutinen, Aleksi | |
dc.contributor.author | Raasakka, Arne | |
dc.contributor.author | Muruganandam, Gopinath | |
dc.contributor.author | Loris, Remy | |
dc.contributor.author | Kursula, Petri | |
dc.date.accessioned | 2022-04-04T13:11:41Z | |
dc.date.available | 2022-04-04T13:11:41Z | |
dc.date.created | 2021-03-09T10:42:08Z | |
dc.date.issued | 2021 | |
dc.identifier.issn | 2296-889X | |
dc.identifier.uri | https://hdl.handle.net/11250/2989684 | |
dc.description.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. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Frontiers Media | en_US |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations | en_US |
dc.type | Journal article | en_US |
dc.type | Peer reviewed | en_US |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2021 Nguyen, Sutinen, Raasakka, Muruganandam, Loris and Kursula | en_US |
dc.source.articlenumber | 631232 | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.doi | 10.3389/fmolb.2020.631232 | |
dc.identifier.cristin | 1896580 | |
dc.source.journal | Frontiers in Molecular Biosciences | en_US |
dc.identifier.citation | Frontiers in Molecular Biosciences. 2021, 7, 631232. | en_US |
dc.source.volume | 7 | en_US |