University of Oulu

Laulumaa, S., Nieminen, T., Raasakka, A., Krokengen, O. C., Safaryan, A., Hallin, E. I., Brysbaert , G., Lensink, M. F., Ruskamo , S., Vattulainen, I., Kursula, P. (2018). Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins. BMC Structural Biology, 18(1).

Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins

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Author: Laulumaa, Saara1,2; Nieminen, Tuomo3; Raasakka, Arne4;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2European Spallation Source (ESS), Lund, Sweden
3Department of Physics, Tampere University of Technology, Tampere, Finland
4Department of Biomedicine, University of Bergen, Bergen, Norway
5Unité de Glycobiologie Structurale et Fonctionnelle, University of Lille, CNRS UMR8576 UGSF, F-59000 Lille, France
6Department of Physics, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2019-06-20


Background: Myelin is a multilayered proteolipid sheath wrapped around selected axons in the nervous system. Its constituent proteins play major roles in forming of the highly regular membrane structure. P2 is a myelin-specific protein of the fatty acid binding protein (FABP) superfamily, which is able to stack lipid bilayers together, and it is a target for mutations in the human inherited neuropathy Charcot-Marie-Tooth disease. A conserved residue that has been proposed to participate in membrane and fatty acid binding and conformational changes in FABPs is Phe57. This residue is thought to be a gatekeeper for the opening of the portal region upon ligand entry and egress.

Results: We performed a structural characterization of the F57A mutant of human P2. The mutant protein was crystallized in three crystal forms, all of which showed changes in the portal region and helix α2. In addition, the behaviour of the mutant protein upon lipid bilayer binding suggested more unfolding than previously observed for wild-type P2. On the other hand, membrane binding rendered F57A heat-stable, similarly to wild-type P2. Atomistic molecular dynamics simulations showed opening of the side of the discontinuous β barrel, giving important indications on the mechanism of portal region opening and ligand entry into FABPs. The results suggest a central role for Phe57 in regulating the opening of the portal region in human P2 and other FABPs, and the F57A mutation disturbs dynamic cross-correlation networks in the portal region of P2.

Conclusions: Overall, the F57A variant presents similar properties to the P2 patient mutations recently linked to Charcot-Marie-Tooth disease. Our results identify Phe57 as a residue regulating conformational changes that may accompany membrane surface binding and ligand exchange in P2 and other FABPs.

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Series: BMC structural biology
ISSN: 1472-6807
ISSN-E: 1472-6807
ISSN-L: 1472-6807
Volume: 18
Article number: 8
DOI: 10.1186/s12900-018-0087-2
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3112 Neurosciences
Funding: This work was funded by grants from the Academy of Finland (#275225, SR), the Academy of Finland Center of Excellence program (#307415, IV), European Research Council (CROWDED-PRO-LIPIDS) (#290974, IV), Sigrid Jusélius Foundation (PK), and Emil Aaltonen Foundation (PK). TN thanks the graduate school of Tampere University of Technology for financial support.
Academy of Finland Grant Number: 275225
Detailed Information: 275225 (Academy of Finland Funding decision)
Copyright information: © The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.