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dc.contributor.authorLaulumaa, Saaraen_US
dc.contributor.authorNieminen, Tuomoen_US
dc.contributor.authorRaasakka, Arneen_US
dc.contributor.authorKrokengen, Oda C.en_US
dc.contributor.authorSafaryan, Anushiken_US
dc.contributor.authorHallin, Erik Ingmaren_US
dc.contributor.authorBrysbaert, Guillaumeen_US
dc.contributor.authorLensink, Marc F.en_US
dc.contributor.authorRuskamo, Sallaen_US
dc.contributor.authorVattulainen, Ilpoen_US
dc.contributor.authorKursula, Petrien_US
dc.PublishedLaulumaa S, Nieminen T, Raasakka A, Krokengen OC, Safaryan A, Hallin EI, Brysbaert, Lensink, Ruskamo S, Vattulainen I, Kursula P. 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;18:8eng
dc.description.abstractBackground: 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.en_US
dc.publisherBioMed Centraleng
dc.rightsAttribution CC BYeng
dc.subjectCrystal structureeng
dc.subjectFatty acid-binding proteineng
dc.subjectMembrane bindingeng
dc.subjectMolecular dynamicseng
dc.subjectProtein stabilityeng
dc.titleStructure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteinsen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2018 The Author(s)
dc.source.journalBMC Structural Biology

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