University of Oulu

Uusitalo, M., Klenow, M.B., Laulumaa, S., Blakeley, M.P., Simonsen, A.C., Ruskamo, S. and Kursula, P. (2021), Human myelin protein P2: from crystallography to time-lapse membrane imaging and neuropathy-associated variants. FEBS J, 288: 6716-6735. https://doi.org/10.1111/febs.16079

Human myelin protein P2 : from crystallography to time-lapse membrane imaging and neuropathy-associated variants

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Author: Uusitalo, Maiju1; Klenow, Martin Berg2; Laulumaa, Saara1,3;
Organizations: 1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
2Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark
3European Spallation Source, Lund, Sweden
4Large-Scale Structures Group, Institut Laue–Langevin, Grenoble, France
5Department of Biomedicine, University of Bergen, Norway
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022012710484
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2022-01-27
Description:

Abstract

Peripheral myelin protein 2 (P2) is a fatty acid-binding protein expressed in vertebrate peripheral nervous system myelin, as well as in human astrocytes. Suggested functions of P2 include membrane stacking and lipid transport. Mutations in the PMP2 gene, encoding P2, are associated with Charcot–Marie–Tooth disease (CMT). Recent studies have revealed three novel PMP2 mutations in CMT patients. To shed light on the structure and function of these P2 variants, we used X-ray and neutron crystallography, small-angle X-ray scattering, circular dichroism spectroscopy, computer simulations and lipid binding assays. The crystal and solution structures of the I50del, M114T and V115A variants of P2 showed minor differences to the wild-type protein, whereas their thermal stability was reduced. Vesicle aggregation assays revealed no change in membrane stacking characteristics, while the variants showed altered fatty acid binding. Time-lapse imaging of lipid bilayers indicated formation of double-membrane structures induced by P2, which could be related to its function in stacking of two myelin membrane surfaces in vivo. In order to better understand the links between structure, dynamics and function, the crystal structure of perdeuterated P2 was refined from room temperature data using neutrons and X-rays, and the results were compared to simulations and cryocooled crystal structures. Our data indicate similar properties for all known human P2 CMT variants; while crystal structures are nearly identical, thermal stability and function of CMT variants are impaired. Our data provide new insights into the structure–function relationships and dynamics of P2 in health and disease.

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Series: FEBS journal
ISSN: 1742-464X
ISSN-E: 1742-4658
ISSN-L: 1742-464X
Volume: 288
Issue: 23
Pages: 6716 - 6735
DOI: doi:10.1111/febs.16079
OADOI: https://oadoi.org/doi:10.1111/febs.16079
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: We acknowledge financial support from the Independent Research Fund Denmark (DFF-FNU), grant no. 7014-00036B (MBK, ACS), Biocenter Oulu (PK, SR, MU), Jane and Aatos Erkko Foundation (PK), and European Spallation Source (PK, SL). The funding sources did not participate in carrying out the research or in the publication process.
Copyright information: © 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  https://creativecommons.org/licenses/by-nc-nd/4.0/