title: Procollagen C-proteinase enhancer-1 (PCPE-1) interacts with beta2-microglobulin (beta2-m) and may help initiate beta2-m amyloid fibril formation in connective tissues.
abstract: Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta(2)-microglobulin (beta2-m) is the major structural component of beta2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhancer-1 (PCPE-1) as a new interacting protein with beta2-m by screening a human synovium cDNA library. The interaction of beta2-m with full-length PCPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta2-m appeared to interact with PCPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta2-m co-localized and formed a complex with PCPE-1. beta2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta2-m amyloid fibril formation from monomeric beta2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta2-m may be linked to subsequent beta2-m amyloid fibril formation, the disruption of the interaction between beta2-m and PCPE-1 may prevent beta2-m amyloid fibril formation and therefore PCPE-1 could be a new target for the treatment of DRA.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Morimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Bernard
authors.initials: B
authors.lastname: Font
authors.forename: Joni D
authors.initials: JD
authors.lastname: Mott
authors.forename: David J S
authors.initials: DJ
authors.lastname: Hulmes
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Ookoshi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasuhara
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakatsuka
authors.forename: Kousuke
authors.initials: K
authors.lastname: Fukuoka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takatori
authors.forename: Haruo
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Akagi
authors.forename: Kazushi
authors.initials: K
authors.lastname: Nakao
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015723:Gene Library; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D020798:Two-Hybrid System Techniques; D001613:beta 2-Microglobulin / Q000737:chemistry*
chemical_list: D000682:Amyloid; D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C491555:PCOLCE protein, human; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1