title: An Intrinsically Disordered Motif Mediates Diverse Actions of Monomeric C-reactive Protein.
abstract: Most proinflammatory actions of C-reactive protein (CRP) are only expressed following dissociation of its native pentameric assembly into monomeric form (mCRP). However, little is known about what underlies the greatly enhanced activities of mCRP. Here we show that a single sequence motif, i.e. cholesterol binding sequence (CBS; a.a. 35-47), is responsible for mediating the interactions of mCRP with diverse ligands. The binding of mCRP to lipoprotein component ApoB, to complement component C1q, to extracellular matrix components fibronectin and collagen, to blood coagulation component fibrinogen, and to membrane lipid component cholesterol, are all found to be markedly inhibited by the synthetic CBS peptide but not by other CRP sequences tested. Likewise, mutating CBS in mCRP also greatly impairs these interactions. Functional experiments further reveal that CBS peptide significantly reduces the effects of mCRP on activation of endothelial cells in vitro and on acute induction of IL-6 in mice. The potency and specificity of CBS are critically determined by the N-terminal residues Cys-36, Leu-37, and His-38; while the versatility of CBS appears to originate from its intrinsically disordered conformation polymorphism. Together, these data unexpectedly identify CBS as the major recognition site of mCRP and suggest that this motif may be exploited to tune the proinflammatory actions of mCRP.
authors.affiliation: From the MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China, State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Fan
authors.initials: F
authors.lastname: Meng
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Zhe-Kun
authors.initials: ZK
authors.lastname: Jia
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China, and.
authors.forename: Qi-Feng
authors.initials: QF
authors.lastname: Bai
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Lv
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and.
authors.forename: Fu-Rong
authors.initials: FR
authors.lastname: Ma
authors.affiliation: Roosevelt University College of Pharmacy, Schaumburg, Illinois 60173.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Potempa
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yong-Bin
authors.initials: YB
authors.lastname: Yan
authors.affiliation: MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and jsr@lzu.edu.cn.
authors.forename: Shang-Rong
authors.initials: SR
authors.lastname: Ji
authors.affiliation: From the MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China, MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences and wuy@lzu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D015850:Interleukin-6; D015922:Complement C1q; D002097:C-Reactive Protein
keywords: C-reactive protein; atherosclerosis; endothelial dysfunction; extracellular matrix; inflammation; intrinsically disordered region; protein motif