a disintegrin and metalloproteinase with thrombospondin motifs; bone morphogenetic protein 1; elastin; extracellular matrix; lysyl oxidase-like 1; proteolysis; Amino Acid Oxidoreductases; LOXL1 protein, human; Protein-Lysine 6-Oxidase; Peptide Hydrolases; ADAMTS Proteins; ADAMTS14 protein, human; BMP1 protein, human; Bone Morphogenetic Protein 1; ADAMTS Proteins/metabolism; Amino Acid Oxidoreductases/genetics; Amino Acid Oxidoreductases/metabolism; Bone Morphogenetic Protein 1/genetics; Bone Morphogenetic Protein 1/metabolism; Humans; Peptide Hydrolases/metabolism; Proteolysis; Proteomics; Exfoliation Syndrome/genetics; Protein-Lysine 6-Oxidase/metabolism; Catalysis; Molecular Biology; Spectroscopy; Computer Science Applications; Physical and Theoretical Chemistry; Organic Chemistry; Inorganic Chemistry; General Medicine
Abstract :
[en] Members of the lysyl oxidase (LOX) family catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin in the initiation step of the formation of covalent cross-links, an essential process for connective tissue maturation. Proteolysis has emerged as an important level of regulation of LOX enzymes with the cleavage of the LOX isoform by metalloproteinases of the BMP1 (bone morphogenetic protein 1) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families as a model example. Lysyl oxidase-like 1 (LOXL1), an isoform associated with pelvic organ prolapse and pseudoexfoliation (PEX) glaucoma, has also been reported to be proteolytically processed by these proteases. However, precise molecular information on these proteolytic events is not available. In this study, using genetic cellular models, along with proteomic analyses, we describe that LOXL1 is processed by BMP1 and ADAMTS14 and identify the processing sites in the LOXL1 protein sequence. Our data show that BMP1 cleaves LOXL1 in a unique location within the pro-peptide region, whereas ADAMTS14 processes LOXL1 in at least three different sites located within the pro-peptide and in the first residues of the catalytic domain. Taken together, these results suggest a complex regulation of LOXL1 function by BMP1- and ADAMTS14-mediated proteolysis where LOXL1 enzymes retaining variable fragments of N-terminal region may display different capabilities.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rosell-García, Tamara ; Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
Rivas-Muñoz, Sergio ; Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Rodriguez-Pascual, Fernando ; Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Científicas (C.S.I.C.), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
Language :
English
Title :
Cleavage of LOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic Processing in the Regulation of LOXL1 Function.
Ministerio de Ciencia e Innovacion, Spain The Glaucoma Foundation
Funding text :
Ministerio de Ciencia e Innovaci?n (Proyecto I+D+I ?Retos Investigaci?n? grant number: RTI2018-095631-B-I00 to F.R-P) and The Glaucoma Foundation (Project: ?Unraveling the proteo-lytic landscape regulating LOXL1. Implications in the development of pseudoexfoliation syn-drome? to F.R-P.). A.C. is a Senior Research Associate of the FRS-FNRS. The APC was funded by Consejo Superior de Investigaciones Cient?ficas (CSIC).Funding: Ministerio de Ciencia e Innovación (Proyecto I+D+I “Retos Investigación” grant number: RTI2018-095631-B-I00 to F.R-P) and The Glaucoma Foundation (Project: “Unraveling the proteo-lytic landscape regulating LOXL1. Implications in the development of pseudoexfoliation syn-drome” to F.R-P.). A.C. is a Senior Research Associate of the FRS-FNRS. The APC was funded by Consejo Superior de Investigaciones Científicas (CSIC).
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