Energetic evaluation of binding modes in the C3d and Factor H (CCP 19-20) complex

As a part of innate immunity, the complement system relies on activation of the alternative pathway (AP). While feed-forward amplification generates an immune response towards foreign surfaces, the process requires regulation to prevent an immune response on the surface of host cells. Factor H (FH)...

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Veröffentlicht in:Protein science 2015-05, Vol.24 (5), p.789-802
Hauptverfasser: E S Harrison, Reed, Gorham, Jr, Ronald D, Morikis, Dimitrios
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Morikis, Dimitrios
description As a part of innate immunity, the complement system relies on activation of the alternative pathway (AP). While feed-forward amplification generates an immune response towards foreign surfaces, the process requires regulation to prevent an immune response on the surface of host cells. Factor H (FH) is a complement protein secreted by native cells to negatively regulate the AP. In terms of structure, FH is composed of 20 complement-control protein (CCP) modules that are structurally homologous but vary in composition and function. Mutations in these CCPs have been linked to states of autoimmunity. In particular, several mutations in CCP 19-20 are correlated to atypical hemolytic uremic syndrome (aHUS). From crystallographic structures there are three putative binding sites of CCP 19-20 on C3d. Since there has been some controversy over the primary mode of binding from experimental studies, we approach characterization of binding using computational methods. Specifically, we compare each binding mode in terms of electrostatic character, structural stability, dissociative and associative properties, and predicted free energy of binding. After a detailed investigation, we found two of the three binding sites to be similarly stable while varying in the number of contacts to C3d and in the energetic barrier to complex dissociation. These sites are likely physiologically relevant and may facilitate multivalent binding of FH CCP 19-20 to C3b and either C3d or host glycosaminoglycans. We propose thermodynamically stable binding with modules 19 and 20, the latter driven by electrostatics, acting synergistically to increase the apparent affinity of FH for host surfaces.
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While feed-forward amplification generates an immune response towards foreign surfaces, the process requires regulation to prevent an immune response on the surface of host cells. Factor H (FH) is a complement protein secreted by native cells to negatively regulate the AP. In terms of structure, FH is composed of 20 complement-control protein (CCP) modules that are structurally homologous but vary in composition and function. Mutations in these CCPs have been linked to states of autoimmunity. In particular, several mutations in CCP 19-20 are correlated to atypical hemolytic uremic syndrome (aHUS). From crystallographic structures there are three putative binding sites of CCP 19-20 on C3d. Since there has been some controversy over the primary mode of binding from experimental studies, we approach characterization of binding using computational methods. 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We propose thermodynamically stable binding with modules 19 and 20, the latter driven by electrostatics, acting synergistically to increase the apparent affinity of FH for host surfaces.</description><subject>Alternative pathway</subject><subject>Atypical Hemolytic Uremic Syndrome - genetics</subject><subject>Atypical Hemolytic Uremic Syndrome - immunology</subject><subject>Autoimmunity</subject><subject>Binding Sites</subject><subject>Complement</subject><subject>Complement activation</subject><subject>Complement C3 Convertase, Alternative Pathway - chemistry</subject><subject>Complement C3d - chemistry</subject><subject>Complement C3d - genetics</subject><subject>Complement C3d - immunology</subject><subject>Complement component C3b</subject><subject>Complement factor H</subject><subject>Complement Factor H - chemistry</subject><subject>Complement Factor H - genetics</subject><subject>Complement Factor H - immunology</subject><subject>Computer applications</subject><subject>Crystal structure</subject><subject>Crystallography</subject><subject>Electrostatic properties</subject><subject>Electrostatics</subject><subject>Free energy</subject><subject>Glycosaminoglycans</subject><subject>Hemolytic uremic syndrome</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunity, Innate</subject><subject>Innate immunity</subject><subject>Models, Molecular</subject><subject>Modules</subject><subject>Mutation</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Structural Homology, Protein</subject><subject>Structural stability</subject><issn>0961-8368</issn><issn>1469-896X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtLxDAUhYMozjgK_gIJuBkX1eSmSZuNIGVGBUEFBXclTdIxQ5vUPgb99xZ8oC5c3cX9-DiHg9AhJaeUEDhr2nAKgpMtNKWxkFEqxdM2mhIpaJQykU7QXtetCSExBbaLJsAFpITDFN0vvG1Xtnca242qBtW74HEoceG8cX6F62Bsh53H_bPFGTNYeYOXSvehxVd4nmV3mMoIyAnWoW4q-7qPdkpVdfbg887Q43LxkF1FN7eX19nFTdQwLvpIM-BUcFnECTHUlCZlUmpqCFNpEjNWiEToksVxyRkT2hoQVioLaSmUoIVgM3T-4W2GorZGW9-3qsqb1tWqfcuDcvnvj3fP-Sps8jiGsXoyCuafgja8DLbr89p12laV8jYMXU7HBFxyxsmIHv9B12Fo_Vgvh4RLSCkA_EeNLk6BjLuM1NHP3N-BvzZh7-QkiVI</recordid><startdate>20150501</startdate><enddate>20150501</enddate><creator>E S Harrison, Reed</creator><creator>Gorham, Jr, Ronald D</creator><creator>Morikis, Dimitrios</creator><general>Wiley Subscription Services, Inc</general><general>BlackWell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QO</scope><scope>7T5</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150501</creationdate><title>Energetic evaluation of binding modes in the C3d and Factor H (CCP 19-20) complex</title><author>E S Harrison, Reed ; Gorham, Jr, Ronald D ; Morikis, Dimitrios</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p356t-c3251659b470d1dfd8399c1d03a87433b676cf344f5336ced26e9ae28f6a61b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alternative pathway</topic><topic>Atypical Hemolytic Uremic Syndrome - genetics</topic><topic>Atypical Hemolytic Uremic Syndrome - immunology</topic><topic>Autoimmunity</topic><topic>Binding Sites</topic><topic>Complement</topic><topic>Complement activation</topic><topic>Complement C3 Convertase, Alternative Pathway - chemistry</topic><topic>Complement C3d - chemistry</topic><topic>Complement C3d - genetics</topic><topic>Complement C3d - immunology</topic><topic>Complement component C3b</topic><topic>Complement factor H</topic><topic>Complement Factor H - chemistry</topic><topic>Complement Factor H - genetics</topic><topic>Complement Factor H - immunology</topic><topic>Computer applications</topic><topic>Crystal structure</topic><topic>Crystallography</topic><topic>Electrostatic properties</topic><topic>Electrostatics</topic><topic>Free energy</topic><topic>Glycosaminoglycans</topic><topic>Hemolytic uremic syndrome</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunity, Innate</topic><topic>Innate immunity</topic><topic>Models, Molecular</topic><topic>Modules</topic><topic>Mutation</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins</topic><topic>Structural Homology, Protein</topic><topic>Structural stability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>E S Harrison, Reed</creatorcontrib><creatorcontrib>Gorham, Jr, Ronald D</creatorcontrib><creatorcontrib>Morikis, Dimitrios</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; 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While feed-forward amplification generates an immune response towards foreign surfaces, the process requires regulation to prevent an immune response on the surface of host cells. Factor H (FH) is a complement protein secreted by native cells to negatively regulate the AP. In terms of structure, FH is composed of 20 complement-control protein (CCP) modules that are structurally homologous but vary in composition and function. Mutations in these CCPs have been linked to states of autoimmunity. In particular, several mutations in CCP 19-20 are correlated to atypical hemolytic uremic syndrome (aHUS). From crystallographic structures there are three putative binding sites of CCP 19-20 on C3d. Since there has been some controversy over the primary mode of binding from experimental studies, we approach characterization of binding using computational methods. Specifically, we compare each binding mode in terms of electrostatic character, structural stability, dissociative and associative properties, and predicted free energy of binding. After a detailed investigation, we found two of the three binding sites to be similarly stable while varying in the number of contacts to C3d and in the energetic barrier to complex dissociation. These sites are likely physiologically relevant and may facilitate multivalent binding of FH CCP 19-20 to C3b and either C3d or host glycosaminoglycans. We propose thermodynamically stable binding with modules 19 and 20, the latter driven by electrostatics, acting synergistically to increase the apparent affinity of FH for host surfaces.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>25628052</pmid><doi>10.1002/pro.2650</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects Alternative pathway
Atypical Hemolytic Uremic Syndrome - genetics
Atypical Hemolytic Uremic Syndrome - immunology
Autoimmunity
Binding Sites
Complement
Complement activation
Complement C3 Convertase, Alternative Pathway - chemistry
Complement C3d - chemistry
Complement C3d - genetics
Complement C3d - immunology
Complement component C3b
Complement factor H
Complement Factor H - chemistry
Complement Factor H - genetics
Complement Factor H - immunology
Computer applications
Crystal structure
Crystallography
Electrostatic properties
Electrostatics
Free energy
Glycosaminoglycans
Hemolytic uremic syndrome
Humans
Immune response
Immune system
Immunity, Innate
Innate immunity
Models, Molecular
Modules
Mutation
Protein Binding
Protein Structure, Tertiary
Proteins
Structural Homology, Protein
Structural stability
title Energetic evaluation of binding modes in the C3d and Factor H (CCP 19-20) complex
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