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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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          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.

          Electronic supplementary material

          The online version of this article (10.1186/s12900-018-0087-2) contains supplementary material, which is available to authorized users.

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          Most cited references46

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          CUPSAT: prediction of protein stability upon point mutations

          CUPSAT (Cologne University Protein Stability Analysis Tool) is a web tool to analyse and predict protein stability changes upon point mutations (single amino acid mutations). This program uses structural environment specific atom potentials and torsion angle potentials to predict ΔΔG, the difference in free energy of unfolding between wild-type and mutant proteins. It requires the protein structure in Protein Data Bank format and the location of the residue to be mutated. The output consists information about mutation site, its structural features (solvent accessibility, secondary structure and torsion angles), and comprehensive information about changes in protein stability for 19 possible substitutions of a specific amino acid mutation. Additionally, it also analyses the ability of the mutated amino acids to adapt the observed torsion angles. Results were tested on 1538 mutations from thermal denaturation and 1603 mutations from chemical denaturation experiments. Several validation tests (split-sample, jack-knife and k-fold) were carried out to ensure the reliability, accuracy and transferability of the prediction method that gives >80% prediction accuracy for most of these validation tests. Thus, the program serves as a valuable tool for the analysis of protein design and stability. The tool is accessible from the link .
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            The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism.

            Fatty acid-binding proteins (FABPs) are members of the superfamily of lipid-binding proteins (LBP). So far 9 different FABPs, with tissue-specific distribution, have been identified: L (liver), I (intestinal), H (muscle and heart), A (adipocyte), E (epidermal), Il (ileal), B (brain), M (myelin) and T (testis). The primary role of all the FABP family members is regulation of fatty acid uptake and intracellular transport. The structure of all FABPs is similar - the basic motif characterizing these proteins is beta-barrel, and a single ligand (e.g. a fatty acid, cholesterol, or retinoid) is bound in its internal water-filled cavity. Despite the wide variance in the protein sequence, the gene structure is identical. The FABP genes consist of 4 exons and 3 introns and a few of them are located in the same chromosomal region. For example, A-FABP, E-FABP and M-FABP create a gene cluster. Because of their physiological properties some FABP genes were tested in order to identify mutations altering lipid metabolism. Furthermore, the porcine A-FABP and H-FABP were studied as candidate genes with major effect on fatness traits.
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              Integrating protein structural dynamics and evolutionary analysis with Bio3D

              Background Popular bioinformatics approaches for studying protein functional dynamics include comparisons of crystallographic structures, molecular dynamics simulations and normal mode analysis. However, determining how observed displacements and predicted motions from these traditionally separate analyses relate to each other, as well as to the evolution of sequence, structure and function within large protein families, remains a considerable challenge. This is in part due to the general lack of tools that integrate information of molecular structure, dynamics and evolution. Results Here, we describe the integration of new methodologies for evolutionary sequence, structure and simulation analysis into the Bio3D package. This major update includes unique high-throughput normal mode analysis for examining and contrasting the dynamics of related proteins with non-identical sequences and structures, as well as new methods for quantifying dynamical couplings and their residue-wise dissection from correlation network analysis. These new methodologies are integrated with major biomolecular databases as well as established methods for evolutionary sequence and comparative structural analysis. New functionality for directly comparing results derived from normal modes, molecular dynamics and principal component analysis of heterogeneous experimental structure distributions is also included. We demonstrate these integrated capabilities with example applications to dihydrofolate reductase and heterotrimeric G-protein families along with a discussion of the mechanistic insight provided in each case. Conclusions The integration of structural dynamics and evolutionary analysis in Bio3D enables researchers to go beyond a prediction of single protein dynamics to investigate dynamical features across large protein families. The Bio3D package is distributed with full source code and extensive documentation as a platform independent R package under a GPL2 license from http://thegrantlab.org/bio3d/. Electronic supplementary material The online version of this article (doi:10.1186/s12859-014-0399-6) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                petri.kursula@uib.no
                Journal
                BMC Struct Biol
                BMC Struct. Biol
                BMC Structural Biology
                BioMed Central (London )
                1472-6807
                25 June 2018
                25 June 2018
                2018
                : 18
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Faculty of Biochemistry and Molecular Medicine, , University of Oulu, ; Oulu, Finland
                [2 ]GRID grid.434715.0, European Spallation Source (ESS), ; Lund, Sweden
                [3 ]ISNI 0000 0000 9327 9856, GRID grid.6986.1, Department of Physics, , Tampere University of Technology, ; Tampere, Finland
                [4 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Biomedicine, , University of Bergen, ; Bergen, Norway
                [5 ]ISNI 0000 0001 2186 1211, GRID grid.4461.7, Unité de Glycobiologie Structurale et Fonctionnelle, , University of Lille, CNRS UMR8576 UGSF, ; F-59000 Lille, France
                [6 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Physics, , University of Helsinki, ; Helsinki, Finland
                Author information
                http://orcid.org/0000-0001-8529-3751
                Article
                87
                10.1186/s12900-018-0087-2
                6020228
                29940944
                343a331b-aa8c-4c95-8cec-940f5b593535
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), 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 ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 March 2018
                : 13 June 2018
                Funding
                Funded by: Academy of Finland (FI)
                Award ID: 275225
                Award Recipient :
                Funded by: Academy of Finland (FI)
                Award ID: 307415
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 290974
                Award Recipient :
                Funded by: Sigrid Juséliuksen Säätiö (FI)
                Funded by: FundRef http://dx.doi.org/10.13039/501100004756, Emil Aaltosen Säätiö;
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Molecular biology
                myelin,crystal structure,fatty acid-binding protein,membrane binding,molecular dynamics,mutation,protein stability

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