title: Coagulation factor XIa cleaves the RHDS sequence and abolishes the cell adhesive properties of the amyloid beta-protein.
abstract: Amyloid beta-protein (A beta) is the major constituent of senile plaques and cerebrovascular amyloid deposits in Alzheimer's disease and is proteolytically derived from its transmembrane parent protein the amyloid beta-protein precursor (A beta PP). Although the physiological role(s) of secreted A beta PPs are not fully understood, several potential functions have been described including the regulation of hemostatic enzymes factors XIa and IXa and a role in cell adhesion. In the present study, we investigated the proteolytic processing of A beta PP by factor XIa (FXIa). Incubation of the human glioblastoma cell line U138 stably transfected to overexpress the 695 isoform of A beta PP with FXIa (2.5-5 nM) resulted in proteolytic cleavage of secreted A beta PP. Higher concentrations of FXIa (> 25 nM) resulted in loss in cell adherence. Coincubation of FXIa with purified, recombinant Kunitz protease inhibitor domain of A beta PP blocked both the proteolytic processing of A beta PP and the loss of cell adhesion. The RHDS cell adhesion site of A beta PP resides within residues 5-8 of the A beta domain. Incubation of synthetic A beta 1-40 peptide with increasing concentrations of FXIa resulted in cleavage of A beta between Arg5 and His6 within the cell adhesion domain of the peptide. FXIa-digested A beta 1-40 or A beta PP695 lost their abilities to serve as cell adhesion substrates consistent with cleavage through this cell adhesion site. Together, these results suggest a new potential biological function for FXIa in the modulation of cell adhesion. In addition, we have shown that FXIa can proteolytically alter A beta and therefore possibly modify its physiological and perhaps pathological properties.
authors.affiliation: Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine 92717-4025, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Saporito-Irwin
authors.forename: W E
authors.initials: WE
authors.lastname: Van Nostrand
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D015945:Factor XIa / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000302:isolation & purification; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009842:Oligopeptides; D010446:Peptide Fragments; D015945:Factor XIa