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Cited by 3Protein Structure and DynamicsMitochondrial Function and PathologyLipid Membrane Structure and Behavior

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Conformational analysis of membrane-proximal segments of GDAP1 in a lipidic environment using synchrotron radiation suggests a mode of assembly at the mitochondrial outer membrane

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Sutinen, Aleksi, Jones, Nykola C., Hoffmann, Søren Vrønning, Ruskamo, Salla, Kursula, Petri·2023·Biophysical Chemistry
DOI 10.1016/j.bpc.2023.107113

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Abstract

The mitochondrial outer membrane creates a diffusion barrier between the cytosol and the mitochondrial intermembrane space, allowing the exchange of metabolic products, important for efficient mitochondrial function in neurons. The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial outer membrane protein with a critical role in mitochondrial dynamics and metabolic balance in neurons. Missense mutations in the GDAP1 gene are linked to the most common human peripheral neuropathy, Charcot-Marie-Tooth disease (CMT). GDAP1 is a distant member of the glutathione-S-transferase (GST) superfamily, with unknown enzymatic properties or functions at the molecular level. The structure of the cytosol-facing GST-like domain has been described, but there is no consensus on how the protein interacts with the mitochondrial outer membrane. Here, we describe a model for GDAP1 assembly on the membrane using peptides vicinal to the GDAP1 transmembrane domain. We used oriented circular dichroism spectroscopy (OCD) with synchrotron radiation to study the secondary structure and orientation of GDAP1 segments at the outer and inner surfaces of the outer mitochondrial membrane. These experiments were complemented by small-angle X-ray scattering, providing the first experimental structural models for full-length human GDAP1. The results indicate that GDAP1 is bound into the membrane via a single transmembrane helix, flanked by two peripheral helices interacting with the outer and inner leaflets of the mitochondrial outer membrane in different orientations. Impairment of these interactions could be a mechanism for CMT in the case of missense mutations affecting these segments instead of the GST-like domain.

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Metadata

Authors
Sutinen, A., Jones, N. C., Hoffmann, S. V., Ruskamo, S., & Kursula, P.
Affiliations
  • University of Oulu (FI)
  • Aarhus University (DK)
  • University of Bergen (NO)
Corresponding author
Kursula, Petri
ORCID
Venue
Biophysical Chemistry
Publisher
Elsevier BV
Published
2023-12
Volume
303
Pages
107113
ISSN
0301-4622 (ISSN-L)
DOI
10.1016/j.bpc.2023.107113
OpenAlex
W4387008138
Cited by
3
References
1
Citations by year
2026: 2 · 2025: 1
FWCI
0.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Biophysical Chemistry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
Funders
  • Horizon 2020 (MOSBRI-2022-76, 101004806)
  • Academy of Finland (24302881)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
GDAP1, mitochondrial outer membrane, protein-membrane interactions, transmembrane helices, Charcot-Marie-Tooth disease, missense mutations, conformational analysis, small-angle X-ray scattering, peripheral neuropathy
MeSH terms
Charcot-Marie-Tooth Disease, Humans, Membrane Proteins, Mitochondria, Neurons, Synchrotrons, Mutation, Missense, Mitochondrial Membranes

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