University of Oulu

Sutinen, A., Nguyen, G. T. T., Raasakka, A., Muruganandam, G., Loris, R., Ylikallio, E., Tyynismaa, H., Bartesaghi, L., Ruskamo, S., & Kursula, P. (2022). Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1. FEBS Open Bio, 12(7), 1306–1324.

Structural insights into Charcot–Marie–Tooth disease-linked mutations in human GDAP1

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Author: Sutinen, Aleksi1; Nguyen, Giang Thi Tuyet1; Raasakka, Arne2;
Organizations: 1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
2Department of Biomedicine, University of Bergen, Norway
3VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
4Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Belgium
5Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Finland
6Clinical Neurosciences, Neurology, Helsinki University Hospital, Finland
7Department of Neuroscience, Karolinska Institutet, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.9 MB)
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Language: English
Published: John Wiley & Sons, 2022
Publish Date: 2023-01-25


Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.

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Series: FEBS open bio
ISSN: 2211-5463
ISSN-E: 2211-5463
ISSN-L: 2211-5463
Volume: 12
Issue: 7
Pages: 1306 - 1324
DOI: 10.1002/2211-5463.13422
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was funded by the Academy of Finland, project number 24302881. The research leading to this result has been supported by the project CALIPSOplus under the Grant Agreement 730872, as well as by iNEXT, grant number 653706, from the EU Framework Program for Research and Innovation HORIZON 2020. We acknowledge the use of the Core Facility for Biophysics, Structural Biology, and Screening (BiSS) at the University of Bergen, which has received funding from the Research Council of Norway (RCN) through the NORCRYST (grant number 245828) infrastructure consortium. The availability of synchrotron beamtime and support on DESY, EMBL/DESY, ISA, and SOLEIL is gratefully acknowledged. Furthermore, we wish to thank Dr. Roman Chrast for project planning and organization.
EU Grant Number: (653706) iNEXT - Infrastructure for NMR, EM and X-rays for translational research
Dataset Reference: The crystal structures and the structure factors have been deposited at the PDB with entry codes 7Q6K (R120W), 7Q6J (H123R), and 7YWD (new crystal form of wtGDAP1). The SAXS data for the GDAP1 mutants are available at the SASBDB under entries SASDND6 (H123R) and SASDNE6 (R120W). The diffraction datasets for the mutants were uploaded on Zenodo: (R120W) and (H123R).
Copyright information: © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.