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Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 29590

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Prof. Dr. Philip C. Trackman

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1. The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA
2. Department of Translational Dental Medicine, School of Dental Medicine, Boston University, 700 Albany Street, Boston, MA 02138, USA
Interests: diabetic bone disease; oral cancer; gingival overgrowth; lysyl oxidases biosynthesis and functions; extracellular matrix biosynthesis; extracellular matrix pathology
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Dear Colleagues,

The lysyl oxidase family of genes consists of five related paralogues, each possessing the active lysyl oxidase enzyme activity domain at the C-terminus of the corresponding proteins. All five enzymes participate in extracellular biosynthetic collagen and elastin cross-linking and maturation critical for normal extracellular structure and function. The N-terminal propeptide regions are more variable between the five paralogues and exhibit their own functions, some of which help coordinate cell signaling and other extracellular and cellular interactions and functions. Some examples include modulation of growth factor signaling, tumor suppression, basement membrane assembly, differentiation and functions of cells as diverse as endothelial cells, osteoblasts and megakaryocytes, macrophages, functional interactions with matricellular proteins, and coordination of elastin biosynthesis. Abnormal regulation, and lysyl oxidase mutations, can result in pathologies including cancer and vascular abnormalities. This volume will bring together new data, ideas and methodologies from active experts which will help to integrate understanding of the latest findings in this field, in both health and disease, which is receiving ever increasing interest and attention.

Prof. Dr. Philip C. Trackman
Guest Editor

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Keywords

lysyl oxidases
cancer
tumor suppression
bone biology
gene polymorphisms and mutations
collagen cross-linking
elastin cross-linking
fibrosis
aneurysm

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Published Papers (12 papers)

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Editorial

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2 pages, 182 KiB

Open AccessEditorial

Multifunctional Lysyl Oxidases

by Philip C. Trackman

Int. J. Mol. Sci. 2023, 24(7), 6044; https://doi.org/10.3390/ijms24076044 - 23 Mar 2023

Cited by 1 | Viewed by 1161

Abstract

This Special Issue on lysyl oxidases, which are proteins derived from five related genes known as Lox, and Loxl1–Loxl4, brings together articles that reflect some of the diverse approaches and perspectives needed to better understand the biology of these multifunctional proteins [...] Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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17 pages, 4417 KiB

Open AccessArticle

Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu²⁺ in the Active Site of Lysyl Oxidase-like 2

by Alex A. Meier, Hee-Jung Moon, Sinan Sabuncu, Priya Singh, Trey A. Ronnebaum, Siyu Ou, Justin T. Douglas, Timothy A. Jackson, Pierre Moënne-Loccoz and Minae Mure

Int. J. Mol. Sci. 2022, 23(22), 13966; https://doi.org/10.3390/ijms232213966 - 12 Nov 2022

Cited by 6 | Viewed by 2147

Abstract

Lysyl oxidase-2 (LOXL2) is a Cu²⁺ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn²⁺-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu²⁺ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu². We propose that LTQ resides within 2.9 Å of the active site of Cu²⁺ in the mature LOXL2, and both LTQ and Cu²⁺ are solvent-exposed. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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19 pages, 6147 KiB

Open AccessArticle

A 3D–Predicted Structure of the Amine Oxidase Domain of Lysyl Oxidase–Like 2

by Alex A. Meier, Krzysztof Kuczera and Minae Mure

Int. J. Mol. Sci. 2022, 23(21), 13385; https://doi.org/10.3390/ijms232113385 - 2 Nov 2022

Cited by 8 | Viewed by 1880

Abstract

Lysyl oxidase–like 2 (LOXL2) has been recognized as an attractive drug target for anti–fibrotic and anti–tumor therapies. However, the structure–based drug design of LOXL2 has been very challenging due to the lack of structural information of the catalytically–competent LOXL2. In this study; we generated a 3D–predicted structure of the C–terminal amine oxidase domain of LOXL2 containing the lysine tyrosylquinone (LTQ) cofactor from the 2.4Å crystal structure of the Zn²⁺–bound precursor (lacking LTQ; PDB:5ZE3); this was achieved by molecular modeling and molecular dynamics simulation based on our solution studies of a mature LOXL2 that is inhibited by 2–hydrazinopyridine. The overall structures of the 3D–modeled mature LOXL2 and the Zn²⁺–bound precursor are very similar (RMSD = 1.070Å), and disulfide bonds are conserved. The major difference of the mature and the precursor LOXL2 is the secondary structure of the pentapeptide (His652–Lys653–Ala654–Ser655–Phe656) containing Lys653 (the precursor residue of the LTQ cofactor). We anticipate that this peptide is flexible in solution to accommodate the conformation that enables the LTQ cofactor formation as opposed to the β–sheet observed in 5ZE3. We discuss the active site environment surrounding LTQ and Cu²⁺ of the 3D–predicted structure. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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20 pages, 3895 KiB

Open AccessArticle

Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes

by Tatyana Liburkin-Dan, Inbal Nir-Zvi, Hila Razon, Ofra Kessler and Gera Neufeld

Int. J. Mol. Sci. 2022, 23(19), 11322; https://doi.org/10.3390/ijms231911322 - 26 Sep 2022

Cited by 1 | Viewed by 2254

Abstract

The five lysyl-oxidase genes share similar enzymatic activities and contribute to tumor progression. We have knocked out the five lysyl-oxidase genes in MDA-MB-231 breast cancer cells using CRISPR/Cas9 in order to identify genes that are regulated by LOX but not by other lysyl-oxidases and in order to study such genes in more mechanistic detail in the future. Re-expression of the full-length cDNA encoding LOX identified four genes whose expression was downregulated in the knock-out cells and rescued following LOX re-expression but not re-expression of other lysyl-oxidases. These were the AGR2, STOX2, DNAJB11 and DNAJC3 genes. AGR2 and STOX2 were previously identified as promoters of tumor progression. In addition, we identified several genes that were not downregulated in the knock-out cells but were strongly upregulated following LOX or LOXL3 re-expression. Some of these, such as the DERL3 gene, also promote tumor progression. There was very little proteolytic processing of the re-expressed LOX pro-enzyme in the MDA-MB-231 cells, while in the HEK293 cells, the LOX pro-enzyme was efficiently cleaved. We introduced point mutations into the known BMP-1 and ADAMTS2/14 cleavage sites of LOX. The BMP-1 mutant was secreted but not cleaved, while the LOX double mutant dmutLOX was not cleaved or secreted. However, even in the presence of the irreversible LOX inhibitor β-aminoproprionitrile (BAPN), these point-mutated LOX variants induced the expression of these genes, suggesting that the LOX pro-enzyme has hitherto unrecognized biological functions. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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20 pages, 4092 KiB

Open AccessArticle

Correlation of Matrisome-Associatted Gene Expressions with LOX Family Members in Astrocytomas Stratified by IDH Mutation Status

by Talita de Sousa Laurentino, Roseli da Silva Soares, Suely Kazue Nagahashi Marie and Sueli Mieko Oba-Shinjo

Int. J. Mol. Sci. 2022, 23(17), 9507; https://doi.org/10.3390/ijms23179507 - 23 Aug 2022

Cited by 6 | Viewed by 2387

Abstract

Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDH^mut), LOXL3 correlations in LGG with IDH wild type (IDH^wt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDH^mut and LGG-IDH^wt through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside–in signaling pathway. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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17 pages, 11310 KiB

Open AccessArticle

Mass Spectrometry-Based Disulfide Mapping of Lysyl Oxidase-like 2

by Alex A. Meier, Eden P. Go, Hee-Jung Moon, Heather Desaire and Minae Mure

Int. J. Mol. Sci. 2022, 23(11), 5879; https://doi.org/10.3390/ijms23115879 - 24 May 2022

Cited by 7 | Viewed by 2097

Abstract

Lysyl oxidase-like 2 (LOXL2) catalyzes the oxidative deamination of peptidyl lysines and hydroxylysines to promote extracellular matrix remodeling. Aberrant activity of LOXL2 has been associated with organ fibrosis and tumor metastasis. The lysine tyrosylquinone (LTQ) cofactor is derived from Lys653 and Tyr689 in the amine oxidase domain via post-translational modification. Based on the similarity in hydrodynamic radius and radius of gyration, we recently proposed that the overall structures of the mature LOXL2 (containing LTQ) and the precursor LOXL2 (no LTQ) are very similar. In this study, we conducted a mass spectrometry-based disulfide mapping analysis of recombinant LOXL2 in three forms: a full-length LOXL2 (fl-LOXL2) containing a nearly stoichiometric amount of LTQ, Δ1-2SRCR-LOXL2 (SRCR1 and SRCR2 are truncated) in the precursor form, and Δ1-3SRCR-LOXL2 (SRCR1, SRCR2, SRCR3 are truncated) in a mixture of the precursor and the mature forms. We detected a set of five disulfide bonds that is conserved in both the precursor and the mature recombinant LOXL2s. In addition, we detected a set of four alternative disulfide bonds in low abundance that is not associated with the mature LOXL2. These results suggest that the major set of five disulfide bonds is retained post-LTQ formation. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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10 pages, 2186 KiB

Open AccessArticle

Loxl2 and Loxl3 Paralogues Play Redundant Roles during Mouse Development

by Patricia G. Santamaría, Pierre Dubus, José Bustos-Tauler, Alfredo Floristán, Alberto Vázquez-Naharro, Saleta Morales, Amparo Cano and Francisco Portillo

Int. J. Mol. Sci. 2022, 23(10), 5730; https://doi.org/10.3390/ijms23105730 - 20 May 2022

Cited by 3 | Viewed by 1805

Abstract

Lysyl oxidase-like 2 (LOXL2) and 3 (LOXL3) are members of the lysyl oxidase family of enzymes involved in the maturation of the extracellular matrix. Both enzymes share a highly conserved catalytic domain, but it is unclear whether they perform redundant functions in vivo. In this study, we show that mice lacking Loxl3 exhibit perinatal lethality and abnormal skeletal development. Additionally, analysis of the genotype of embryos carrying double knockout of Loxl2 and Loxl3 genes suggests that both enzymes have overlapping functions during mouse development. Furthermore, we also show that ubiquitous expression of Loxl2 suppresses the lethality associated with Loxl3 knockout mice. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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20 pages, 3499 KiB

Open AccessArticle

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

by Yimin Yao, Alison Findlay, Jessica Stolp, Benjamin Rayner, Kjetil Ask and Wolfgang Jarolimek

Int. J. Mol. Sci. 2022, 23(10), 5533; https://doi.org/10.3390/ijms23105533 - 16 May 2022

Cited by 18 | Viewed by 3787

Abstract

Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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17 pages, 3886 KiB

Open AccessArticle

Cleavage of LOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic Processing in the Regulation of LOXL1 Function

by Tamara Rosell-García, Sergio Rivas-Muñoz, Alain Colige and Fernando Rodriguez-Pascual

Int. J. Mol. Sci. 2022, 23(6), 3285; https://doi.org/10.3390/ijms23063285 - 18 Mar 2022

Cited by 5 | Viewed by 2503

Abstract

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. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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Review

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18 pages, 360 KiB

Open AccessReview

Lysyl Oxidase Family Proteins: Prospective Therapeutic Targets in Cancer

by Wei Wang, Xiangjun Wang, Feng Yao and Chao Huang

Int. J. Mol. Sci. 2022, 23(20), 12270; https://doi.org/10.3390/ijms232012270 - 14 Oct 2022

Cited by 22 | Viewed by 3214

Abstract

The lysyl oxidase (LOX) family, consisting of LOX and LOX-like proteins 1–4 (LOXL1–4), is responsible for the covalent crosslinking of collagen and elastin, thus maintaining the stability of the extracellular matrix (ECM) and functioning in maintaining connective tissue function, embryonic development, and wound healing. Recent studies have found the aberrant expression or activity of the LOX family occurs in various types of cancer. It has been proved that the LOX family mainly performs tumor microenvironment (TME) remodeling function and is extensively involved in tumor invasion and metastasis, immunomodulation, proliferation, apoptosis, etc. With relevant translational research in progress, the LOX family is expected to be an effective target for tumor therapy. Here, we review the research progress of the LOX family in tumor progression and therapy to provide novel insights for future exploration of relevant tumor mechanism and new therapeutic targets. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

10 pages, 1279 KiB

Open AccessReview

Lysyl Oxidases: Orchestrators of Cellular Behavior and ECM Remodeling and Homeostasis

by Shelly Zaffryar-Eilot and Peleg Hasson

Int. J. Mol. Sci. 2022, 23(19), 11378; https://doi.org/10.3390/ijms231911378 - 27 Sep 2022

Cited by 9 | Viewed by 2117

Abstract

Lysyl oxidases have long been considered key secreted extracellular matrix modifying enzymes. As such, their activity has been associated with the crosslinking of collagens and elastin, and as a result, they have been linked to multiple developmental and pathological processes. However, numerous lines of evidence also demonstrated that members of this enzyme family are localized and are active within the cytoplasm or cell nuclei, where they regulate and participate in distinct cellular events. In this review, we focus on a few of these events and highlight the intracellular role these enzymes play. Close examination of these events, suggest that the intracellular activities of lysyl oxidases is mostly observed in processes where concomitant changes in the extracellular matrix takes place. Here, we suggest that the LOX family members act in the relay between changes in the cells’ environment and the intracellular processes that promote them or that follow. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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12 pages, 1260 KiB

Open AccessReview

Functions and Mechanisms of Pro-Lysyl Oxidase Processing in Cancers and Eye Pathologies with a Focus on Diabetic Retinopathy

by Philip C. Trackman, Yaser Peymanfar and Sayon Roy

Int. J. Mol. Sci. 2022, 23(9), 5088; https://doi.org/10.3390/ijms23095088 - 3 May 2022

Cited by 5 | Viewed by 2848

Abstract

Lysyl oxidases are multifunctional proteins derived from five lysyl oxidase paralogues (LOX) and lysyl oxidase-like 1 through lysyl oxidase-like 4 (LOXL1–LOXL4). All participate in the biosynthesis of and maturation of connective tissues by catalyzing the oxidative deamination of lysine residues in collagens and elastin, which ultimately results in the development of cross-links required to function. In addition, the five LOX genes have been linked to fibrosis and cancer when overexpressed, while tumor suppression by the propeptide derived from pro-LOX has been documented. Similarly, in diabetic retinopathy, LOX overexpression, activity, and elevated LOX propeptide have been documented. The proteolytic processing of pro-forms of the respective proteins is beginning to draw attention as the resultant peptides appear to exhibit their own biological activities. In this review we focus on the LOX paralogue, and what is known regarding its extracellular biosynthetic processing and the still incomplete knowledge regarding the activities and mechanisms of the released lysyl oxidase propeptide (LOX-PP). In addition, a summary of the roles of both LOX and LOX-PP in diabetic retinopathy, and brief mentions of the roles for LOX and closely related LOXL1 in glaucoma, and keratoconus, respectively, are included. Full article

(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins)

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