A Novel Proteolytic Processing of Prolysyl Oxidase

Atsawasuwan, Phimon; Mochida, Yoshiyuki; Katafuchi, Michitsuna; Tokutomi, Kentaro; Mocanu, Viorel; Parker, Carol E.; Yamauchi, Mitsuo

doi:10.3109/03008207.2011.564337

Cited by 9 publications

(6 citation statements)

References 22 publications

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“…The human LOX precursor is synthesized as a 48-kDa pro-protein, and following extensive intracellular and extracellular processing, procollagen C-protease, which is also known as bone morphogenic protein 1 (BMP1), proteolytically cleaves the LOX precursor into an enzymatically active 32-kDa protein in the extracellular matrix (25)(26)(27). As previously demonstrated, BMP1 is an astacin metalloprotease that plays an important role in extracellular matrix remodeling and osteogenesis (28,29).…”

Section: Discussionmentioning

confidence: 94%

Lysyl oxidase modulates the osteoblast differentiation of primary mouse calvaria cells

Sharma-Bhandari

Park

Kim

et al. 2015

International Journal of Molecular Medicine

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Lysyl oxidase (LOX) is an extracellular amine oxidase that mediates the formation of collagen fibers. Thus far, five LOX family genes [LOX, lysyl oxidase-like (LOXL)1, LOXL2, LOXL3 and LOXL4] have been identified in humans, each encoding the characteristic C-terminal domains that are required for amine oxidase activity. During osteoblastogenesis, collagen fibers function as a three-dimensional scaffold for organizing mineral deposition. In this study, to assess the functional roles of the LOX family members in osteoblastogenesis, we investigated the temporal expression of these genes as a function of phenotypic development during the osteoblast differentiation of primary cultured mouse calvaria cells. Of the LOX family members, only LOX was prominently expressed during osteoblast differentiation. LOX expression was highest on day 9 of differentiation, as shown by RT-PCR and western blot analysis. The expression pattern of collagen, type I, alpha 2 (COL1A2), which encodes the α2-chain of mouse collagen type I, was similar to that of LOX. The total amine oxidase activity of the differentiating calvaria cells exhibited a temporal pattern that paralleled LOX expression, reaching the highest level on day 9 of differentiation. We also noted that the inhibition of the amine oxidase activity of LOX significantly suppressed both mineral nodule formation and the expression of osteoblast marker genes during the differentiation of primary calvaria cells. Taken together, these findings suggest that the LOX-mediated organization of collagen fibers in the extracellular matrix is an important regulator of osteoblastogenesis.

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Section: Discussionmentioning

confidence: 94%

Lysyl oxidase modulates the osteoblast differentiation of primary mouse calvaria cells

Sharma-Bhandari

Park

Kim

et al. 2015

International Journal of Molecular Medicine

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“…Tyrosine O-sulfation is one of the PTMs known to add extra negative charges and has been increasingly recognized as an important regulator of protein-protein interactions in the extracellular space (18,19). In fact, tyrosine sulfation of LOX in this particular location has been previously suggested but, to our knowledge, not thoroughly investigated (20). Analysis of LOX sequence using Sulfinator, a software used to predict tyrosine sulfation sites, revealed candidate tyrosines for this modification in a cluster within this region ( Fig.…”

Section: Identification Of Tyrosine Sulfation In the Region Of Lox Prmentioning

confidence: 93%

Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain

Rosell-García

Paradela

Bravo

et al. 2019

Journal of Biological Chemistry

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Edited by Gerald W. HartCollagens are the main structural component of the extracellular matrix and provide biomechanical properties to connective tissues. A critical step in collagen fibril formation is the proteolytic removal of N-and C-terminal propeptides from procollagens by metalloproteinases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and BMP1 (bone morphogenetic protein 1)/Tolloidlike families, respectively. BMP1 also cleaves and activates the lysyl oxidase (LOX) precursor, the enzyme catalyzing the initial step in the formation of covalent collagen crosslinks, an essential process for fibril stabilization. In this study, using murine skin fibroblasts and HEK293 cells, along with immunoprecipitation, LOX enzymatic activity, solidphase 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. We noted that the LOX sequence between the BMP1-and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are posttranslationally modified by tyrosine O-sulfation and contribute to binding to collagen. Taken together, these findings unravel an additional level of regulation in the formation of collagen fibrils. They point to a mechanism that controls the binding of LOX to collagen and is based on differential BMP1-and ADAMTS2/14-mediated cleavage of a tyrosinesulfated domain.

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“…ProLOX is processed extracellularly by BMP1/Tolloid-like proteinases, the same proteinases that cleave the C-propeptide of type I procollagen, to produce an active mature ~30 kDa LOX. Recently, an additional processing of proLOX has been reported, resulting in a truncated form of active LOX, although its biological function is not clear at present [68]. The N-terminal propeptide of LOX has been implicated in regulating the localization of the enzyme, suppressing tumours and inhibiting cell proliferation [69–71].…”

Section: Extracellular Lysine Modificationsmentioning

confidence: 99%

Lysine post-translational modifications of collagen

Yamauchi

Sricholpech

2012

Essays in Biochemistry

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472

497

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Type I collagen is the most abundant structural protein in vertebrates. It is a heterotrimeric molecule composed of two α1 chains and one α2 chain, forming a long uninterrupted triple helical structure with short non-triple helical telopeptides at both the N- and C-termini. During biosynthesis, collagen acquires a number of post-translational modifications, including lysine modifications, that are critical to the structure and biological functions of this protein. Lysine modifications of collagen are highly complicated sequential processes catalysed by several groups of enzymes leading to the final step of biosynthesis, covalent intermolecular cross-linking. In the cell, specific lysine residues are hydroxylated to form hydroxylysine. Then specific hydroxylysine residues located in the helical domain of the molecule are glycosylated by the addition of galactose or glucose-galactose. Outside the cell, lysine and hydroxylysine residues in the N- and C-telopeptides can be oxidatively deaminated to produce reactive aldehydes that undergo a series of non-enzymatic condensation reactions to form covalent intra- and inter-molecular cross-links. Owing to the recent advances in molecular and cellular biology, and analytical technologies, the biological significance and molecular mechanisms of these modifications have been gradually elucidated. This chapter provides an overview on these enzymatic lysine modifications and subsequent cross-linking.

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A Novel Proteolytic Processing of Prolysyl Oxidase

Cited by 9 publications

References 22 publications

Lysyl oxidase modulates the osteoblast differentiation of primary mouse calvaria cells

Lysyl oxidase modulates the osteoblast differentiation of primary mouse calvaria cells

Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain

Lysine post-translational modifications of collagen

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