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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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Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins. / Laulumaa, Saara; Nieminen, Tuomo; Raasakka, Arne; Krokengen, Oda C.; Safaryan, Anushik; Hallin, Erik I.; Brysbaert, Guillaume; Lensink, Marc F.; Ruskamo, Salla; Vattulainen, Ilpo; Kursula, Petri.

In: BMC Structural Biology, Vol. 18, No. 1, 8, 25.06.2018.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Laulumaa, S, Nieminen, T, Raasakka, A, Krokengen, OC, Safaryan, A, Hallin, EI, Brysbaert, G, Lensink, MF, 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, vol. 18, no. 1, 8. https://doi.org/10.1186/s12900-018-0087-2

APA

Laulumaa, S., Nieminen, T., Raasakka, A., Krokengen, O. C., Safaryan, A., Hallin, E. 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), [8]. https://doi.org/10.1186/s12900-018-0087-2

Vancouver

Laulumaa S, Nieminen T, Raasakka A, Krokengen OC, Safaryan A, Hallin EI et al. 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. 2018 Jun 25;18(1). 8. https://doi.org/10.1186/s12900-018-0087-2

Author

Laulumaa, Saara ; Nieminen, Tuomo ; Raasakka, Arne ; Krokengen, Oda C. ; Safaryan, Anushik ; Hallin, Erik I. ; Brysbaert, Guillaume ; Lensink, Marc F. ; Ruskamo, Salla ; Vattulainen, Ilpo ; Kursula, Petri. / Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins. In: BMC Structural Biology. 2018 ; Vol. 18, No. 1.

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@article{94491b466ee246e7aaca12ae8818d473,
title = "Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins",
abstract = "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.",
keywords = "Crystal structure, Fatty acid-binding protein, Membrane binding, Molecular dynamics, Mutation, Myelin, Protein stability",
author = "Saara Laulumaa and Tuomo Nieminen and Arne Raasakka and Krokengen, {Oda C.} and Anushik Safaryan and Hallin, {Erik I.} and Guillaume Brysbaert and Lensink, {Marc F.} and Salla Ruskamo and Ilpo Vattulainen and Petri Kursula",
year = "2018",
month = "6",
day = "25",
doi = "10.1186/s12900-018-0087-2",
language = "English",
volume = "18",
journal = "BMC Structural Biology",
issn = "1472-6807",
publisher = "Springer Verlag",
number = "1",

}

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TY - JOUR

T1 - Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins

AU - Laulumaa, Saara

AU - Nieminen, Tuomo

AU - Raasakka, Arne

AU - Krokengen, Oda C.

AU - Safaryan, Anushik

AU - Hallin, Erik I.

AU - Brysbaert, Guillaume

AU - Lensink, Marc F.

AU - Ruskamo, Salla

AU - Vattulainen, Ilpo

AU - Kursula, Petri

PY - 2018/6/25

Y1 - 2018/6/25

N2 - 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.

AB - 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.

KW - Crystal structure

KW - Fatty acid-binding protein

KW - Membrane binding

KW - Molecular dynamics

KW - Mutation

KW - Myelin

KW - Protein stability

U2 - 10.1186/s12900-018-0087-2

DO - 10.1186/s12900-018-0087-2

M3 - Article

VL - 18

JO - BMC Structural Biology

JF - BMC Structural Biology

SN - 1472-6807

IS - 1

M1 - 8

ER -