Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
UniProtKB reviewed entry P28300 (LYOX_HUMAN), protein-lysine 6-oxidase
-
Curated human LOX function is oxidative deamination of peptidyl lysines in collagen and elastin precursors.
"Responsible for the post-translational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin"
-
Curated human LOX localization is secreted extracellular space.
"Secreted, extracellular space."
-
BMP1 removes the LOX propeptide, while ADAMTS2 and ADAMTS14 make an additional downstream cleavage.
"Proteolytically cleaved by BMP1 which removes the propeptide (PubMed:31152061). Also proteolytically cleaved by ADAMTS2 and ADAMTS14, but not by ADAMTS3, at an additional cleavage site downstream of the BMP1 cleavage site (PubMed:31152061)."
-
Differential LOX processing regulates collagen binding.
"Cleavage by BMP1 to remove the propeptide does not increase enzymatic activity but increases binding to collagen (PubMed:31152061). Cleavage by ADAMTS2 produces a form with reduced collagen-binding activity (PubMed:31152061)."
Characterization of the human lysyl oxidase gene locus.
-
Human LOX is a copper-dependent collagen- and elastin-cross-linking enzyme; the locus produces multiple alternatively spliced transcripts.
"Lysyl oxidase (EC 1.4.3.13) is a copper-dependent enzyme acting principally on collagen and elastin catalyzing the formation of aldehyde cross-links."
The complete derived amino acid sequence of human lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine ras recision gene).
-
Human LOX oxidizes lysine to an aldehyde that initiates covalent collagen and tropoelastin cross-linking in the extracellular matrix.
"Lysyl oxidase catalyzes the oxidation of lysine residues to alpha-aminoadipic-delta-semialdehyde. This is the first step in the covalent cross-linking of collagen and tropoelastin and results in the formation of insoluble collagen and elastic fibers in the extracellular matrix."
Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2.
-
Human LOX initiates collagen and elastin cross-linking by oxidative deamination of selected lysine and hydroxylysine epsilon-amino groups.
"Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues."
-
The cloned 417-residue human precursor includes a 21-residue signal peptide.
"This cDNA encodes a polypeptide of 417 amino acid residues, including a signal peptide of 21 amino acids."
Elastic fibres in health and disease.
Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic response of vascular smooth muscle cells.
-
In cultured rat aortic smooth-muscle cells, inhibiting LOX reduced chemotaxis toward LOX and PDGF-BB, while sub-chemotactic LOX enhanced the PDGF-BB response.
"Here we demonstrate that inhibition of LOX activity by beta-aminopropionitrile (BAPN) in cultured rat aortic smooth muscle cells (SMCs) reduced the chemotactic response and sensitivity of these cells toward LOX and toward PDGF-BB. The chemotactic activity of PDGF-BB was significantly enhanced in the presence of a non-chemotactic concentration of LOX."
-
LOX-dependent oxidation of cell-surface PDGFR-beta altered ligand binding and downstream signaling kinetics in rat SMCs, with LOX-knockout mouse embryonic fibroblasts providing orthogonal support.
"These novel findings suggest that LOX activity is essential to generate optimal chemotactic sensitivity of cells to chemoattractants by oxidizing specific cell surface proteins, such as PDGFR-beta."
Differential regulation of elastic fiber formation by fibulin-4 and -5.
-
Human fibulin-4 directly binds LOX and promotes a ternary complex with tropoelastin that can target elastin cross-linking.
"Novel findings are that fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking."
Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase.
-
Fibulin-4 binds the LOX propeptide and promotes assembly of LOX onto tropoelastin.
"We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin."
The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine phosphatase kappa and inhibits β-catenin transcriptional activity in lung cancer cells.
-
LOX propeptide directly interacts with the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa in mammalian cells.
"Here, a yeast two-hybrid assay of LOX-PP-interacting proteins identified a clone encoding the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP-κ), and the interaction of the two proteins in mammalian cells was confirmed."
Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein.
Nuclear translocation of lysyl oxidase is promoted by interaction with transcription repressor p66β.
-
Co-expression with p66β drives nuclear accumulation of LOX in tumor cells, after direct interaction with the LOX catalytic domain.
"Moreover, co-expression of p66β and LOX in living tumor cells leads to the nuclear accumulation of LOX."
Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation.
LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.
-
Human disease-associated catalytic-domain LOX variants have significantly reduced lysyl oxidase activity.
"Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein."
-
Rare LOX variants predispose to thoracic aortic disease, supporting a physiological requirement for LOX in aortic-wall integrity.
"These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease."
Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa.
-
Fibulin-4 binds LOX and LOXL1, and the E57K fibulin-4 mutation strongly reduces binding to the LOX propeptide.
"We show that fibulin-4 binds stronger than fibulin-3 and -5 to LTBP1s, 3, and 4s, and to the lysyl oxidases LOX and LOXL1; the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K."
Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners.
-
Recombinant human LOX propeptide is elongated, monomeric, intrinsically disordered, and flexible.
"We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm)."
-
Human LOX propeptide directly binds multiple extracellular-matrix proteins and matrix-associated enzymes in vitro.
"We have identified 17 new partners of LOX-PP including four GAGs (chondroitin sulfate, dermatan sulfate, heparan sulfate, hyaluronan), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, and MMP-2), one proteoglycan (fibromodulin), one matricryptin (anastellin),"
Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain.
-
BMP1 activates proLOX, whereas ADAMTS2/14 make a second downstream cleavage in expressed LOX.
"In this study, using murine skin fibroblasts and HEK293 cells, along with immunoprecipitation, LOX enzymatic activity, solid-phase binding assays, and proteomics analyses, we report that the LOX precursor is proteolytically processed by the procollagen N-proteinases ADAMTS2 and ADAMTS14 between Asp-218 and Tyr-219, 50 amino acids downstream of the BMP1 cleavage site."
-
Sulfated tyrosines in the segment between the BMP1 and ADAMTS cleavage sites contribute to LOX collagen binding.
"We noted that the LOX sequence between the BMP1- and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen."
Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans.
-
A human LOX missense allele segregates with thoracic aortic disease, and the homologous engineered mouse allele disrupts elastic lamellae and causes severe aortic disease when homozygous.
"Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage."
-
The authors infer that insufficient collagen and elastin cross-linking explains LOX-associated aortic-wall weakness.
"These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall."
Formation of allysine by LOX
Prolysyl oxidase activation
Elastin cross-linking by lysyl oxidase
Formation of hydroxyallysine by LOX