title: CLAC binds to amyloid beta peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils.
abstract: CLAC (collagenous Alzheimer amyloid plaque component) is a proteolytic fragment derived from a novel membrane-bound collagen, CLAC-P/collagen type XXV, that deposits in senile plaques associated with amyloid beta peptides (Abeta) in the brains of patients with Alzheimer's disease. We previously showed that CLAC binds to the fibrillized form of Abeta in vitro, although the mechanism and the subdomains that mediate interaction of CLAC with Abeta as well as the effect of binding of CLAC on amyloid fibril formation remain unknown. Here we show that the collagenous domain 1 of CLAC, which is rich in positively charged amino acid residues, mediates its interaction with Abeta and that this binding is mediated by an electrostatic interaction and requires formation of the triple helix structure of CLAC. The soluble form of CLAC purified from the media of cells transfected with CLAC-P inhibited fibrillization of Abeta in vitro, especially in its elongation phase. These results suggest the anti-amyloidogenic roles of CLAC in the pathophysiology of Alzheimer's disease.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo Bunkyoku Tokyo, 113-0033, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Osada
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishimura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D002460:Cell Line; D003094:Collagen / Q000737:chemistry; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D008854:Microscopy, Electron; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D024041:Non-Fibrillar Collagens / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012965:Sodium Chloride / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D055672:Static Electricity; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; C456021:COL25A1 protein, human; D017077:Culture Media, Conditioned; D024041:Non-Fibrillar Collagens; D013844:Thiazoles; C009462:thioflavin T; D012965:Sodium Chloride; D006493:Heparin; D003094:Collagen; D004247:DNA; D014357:Trypsin