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Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV.
López-Jiménez AJ, Basak T, Vanacore RM
(2017) J Biol Chem 292: 16970-16982
MeSH Terms: Amino Acid Oxidoreductases, Basement Membrane, Collagen Type IV, Extracellular Matrix, HEK293 Cells, Humans, Mutagenesis, Site-Directed, Protein Domains, Protein Processing, Post-Translational, Proteolysis
Show Abstract · Added November 3, 2017
Lysyl oxidase-like-2 (LOXL2) is an enzyme secreted into the extracellular matrix that crosslinks collagens by mediating oxidative deamination of lysine residues. Our previous work demonstrated that this enzyme crosslinks the 7S domain, a structural domain that stabilizes collagen IV scaffolds in the basement membrane. Despite its relevant role in extracellular matrix biosynthesis, little is known about the structural requirements of LOXL2 that enable collagen IV crosslinking. In this study, we demonstrate that LOXL2 is processed extracellularly by serine proteases, generating a 65-kDa form lacking the first two scavenger receptor cysteine-rich domains. Site-specific mutagenesis to prevent proteolytic processing generated a full-length enzyme that is active toward a soluble substrate, but fails to crosslink insoluble collagen IV within the extracellular matrix. In contrast, the processed form of LOXL2 binds to collagen IV and crosslinks the 7S domain. Together, our data demonstrate that proteolytic processing is an important event that allows LOXL2-mediated crosslinking of basement membrane collagen IV.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
0 Resources
10 MeSH Terms
Building collagen IV smart scaffolds on the outside of cells.
Brown KL, Cummings CF, Vanacore RM, Hudson BG
(2017) Protein Sci 26: 2151-2161
MeSH Terms: Amino Acid Motifs, Amino Acid Oxidoreductases, Animals, Antigens, Neoplasm, Basement Membrane, Collagen Type IV, Eukaryotic Cells, Extracellular Matrix, Gene Expression Regulation, Humans, Peroxidases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Receptors, Interleukin-1
Show Abstract · Added November 2, 2017
Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
© 2017 The Protein Society.
1 Communities
1 Members
0 Resources
16 MeSH Terms
Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR
(2017) Nature 545: 243-247
MeSH Terms: Animals, Anti-Glomerular Basement Membrane Disease, Autoimmunity, Base Sequence, CD4-Positive T-Lymphocytes, Collagen Type IV, Cytokines, Female, Forkhead Transcription Factors, HLA-DR Serological Subtypes, HLA-DR1 Antigen, Humans, Immunodominant Epitopes, Male, Mice, Mice, Transgenic, Models, Molecular, T-Lymphocytes, Regulatory
Show Abstract · Added June 2, 2017
Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4 T-cell self-epitope derived from the α3 chain of type IV collagen (α3). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3-specific T cells expand in patients with Goodpasture disease and, in α3-immunized HLA-DR15 transgenic mice, α3-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3 epitope in different binding registers. HLA-DR15-α3 tetramer T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3 tetramer T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4Foxp3 regulatory T cells (T cells) expressing tolerogenic cytokines. HLA-DR1-induced T cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15 and HLA-DR1 healthy human donors display altered α3-specific T-cell antigen receptor usage, HLA-DR15-α3 tetramer Foxp3 T and HLA-DR1-α3 tetramer Foxp3CD25CD127 T dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3-specific CD4 T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific T cells that leads to protection or causation of autoimmunity.
1 Communities
1 Members
0 Resources
18 MeSH Terms
The sulfilimine cross-link of collagen IV contributes to kidney tubular basement membrane stiffness.
Bhave G, Colon S, Ferrell N
(2017) Am J Physiol Renal Physiol 313: F596-F602
MeSH Terms: Animals, Basement Membrane, Biomechanical Phenomena, Collagen Type IV, Cross-Linking Reagents, Elastic Modulus, Extracellular Matrix Proteins, Genotype, Imines, Kidney, Mice, Inbred C57BL, Mice, Knockout, Peroxidase, Phenotype, Protein Conformation, Tensile Strength
Show Abstract · Added December 7, 2017
Basement membranes (BMs), a specialized form of extracellular matrix, underlie nearly all cell layers and provide structural support for tissues and interact with cell surface receptors to determine cell behavior. Both macromolecular composition and stiffness of the BM influence cell-BM interactions. Collagen IV is a major constituent of the BM that forms an extensively cross-linked oligomeric network. Its deficiency leads to BM mechanical instability, as observed with glomerular BM in Alport syndrome. These findings have led to the hypothesis that collagen IV and its cross-links determine BM stiffness. A sulfilimine bond (S = N) between a methionine sulfur and a lysine nitrogen cross-links collagen IV and is formed by the matrix enzyme peroxidasin. In peroxidasin knockout mice with reduced collagen IV sulfilimine cross-links, we find a reduction in renal tubular BM stiffness. Thus this work provides the first direct experimental evidence that collagen IV sulfilimine cross-links contribute to BM mechanical properties and provides a foundation for future work on the relationship of BM mechanics to cell function in renal disease.
Copyright © 2017 the American Physiological Society.
1 Communities
0 Members
0 Resources
16 MeSH Terms
Collagen IV and basement membrane at the evolutionary dawn of metazoan tissues.
Fidler AL, Darris CE, Chetyrkin SV, Pedchenko VK, Boudko SP, Brown KL, Gray Jerome W, Hudson JK, Rokas A, Hudson BG
(2017) Elife 6:
MeSH Terms: Animals, Basement Membrane, Collagen Type IV, Ctenophora, Evolution, Molecular, Extracellular Matrix
Show Abstract · Added April 19, 2017
The role of the cellular microenvironment in enabling metazoan tissue genesis remains obscure. Ctenophora has recently emerged as one of the earliest-branching extant animal phyla, providing a unique opportunity to explore the evolutionary role of the cellular microenvironment in tissue genesis. Here, we characterized the extracellular matrix (ECM), with a focus on collagen IV and its variant, spongin short-chain collagens, of non-bilaterian animal phyla. We identified basement membrane (BM) and collagen IV in Ctenophora, and show that the structural and genomic features of collagen IV are homologous to those of non-bilaterian animal phyla and Bilateria. Yet, ctenophore features are more diverse and distinct, expressing up to twenty genes compared to six in vertebrates. Moreover, collagen IV is absent in unicellular sister-groups. Collectively, we conclude that collagen IV and its variant, spongin, are primordial components of the extracellular microenvironment, and as a component of BM, collagen IV enabled the assembly of a fundamental architectural unit for multicellular tissue genesis.
1 Communities
5 Members
1 Resources
6 MeSH Terms
The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease.
Xie LJ, Cui Z, Chen FJ, Pei ZY, Hu SY, Gu QH, Jia XY, Zhu L, Zhou XJ, Zhang H, Liao YH, Lai LH, Hudson BG, Zhao MH
(2017) Immunology 151: 395-404
MeSH Terms: Alleles, Anti-Glomerular Basement Membrane Disease, Autoantigens, China, Collagen Type IV, Computer Simulation, Epitope Mapping, Epitopes, T-Lymphocyte, Genetic Predisposition to Disease, Genotype, HLA-DRB1 Chains, Humans, Polymorphism, Genetic, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell, Risk, T-Lymphocytes
Show Abstract · Added May 12, 2017
Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4·6, P = 5·7 × 10 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10 ) on DRβ1, encoded by DRB1*1501, were associated with disease susceptibility. α (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine , tryptophan , glycine , phenylalanine and phenylalanine , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRβ1 chain and presenting T-cell epitope, α , with five critical residues.
© 2017 John Wiley & Sons Ltd.
1 Communities
1 Members
1 Resources
18 MeSH Terms
The nature and biology of basement membranes.
Pozzi A, Yurchenco PD, Iozzo RV
(2017) Matrix Biol 57-58: 1-11
MeSH Terms: Agrin, Animals, Basement Membrane, Bone Diseases, Developmental, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Gene Expression Regulation, Heparan Sulfate Proteoglycans, Humans, Laminin, Lupus Nephritis, Mechanotransduction, Cellular, Membrane Glycoproteins, Mutation, Protein Isoforms
Show Abstract · Added March 26, 2017
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Copyright © 2017 Elsevier B.V. All rights reserved.
0 Communities
0 Members
1 Resources
16 MeSH Terms
Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis.
Borza CM, Su Y, Tran TL, Yu L, Steyns N, Temple KJ, Skwark MJ, Meiler J, Lindsley CW, Hicks BR, Leitinger B, Zent R, Pozzi A
(2017) Matrix Biol 57-58: 258-271
MeSH Terms: Acute Kidney Injury, Angiotensins, Animals, Binding Sites, Collagen Type IV, Discoidin Domain Receptor 1, Epithelial Cells, Gene Expression Regulation, Humans, Kidney Glomerulus, Male, Mice, Mice, Knockout, Nephrectomy, Nephritis, Protein Binding, Signal Transduction, Ureter, Ureteral Obstruction
Show Abstract · Added March 26, 2017
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagens. DDR1 expression increases following kidney injury and accumulating evidence suggests that it contributes to the progression of injury. To this end, deletion of DDR1 is beneficial in ameliorating kidney injury induced by angiotensin infusion, unilateral ureteral obstruction, or nephrotoxic nephritis. Most of the beneficial effects observed in the DDR1-null mice are attributed to reduced inflammatory cell infiltration to the site of injury, suggesting that DDR1 plays a pro-inflammatory effect. The goal of this study was to determine whether, in addition to its pro-inflammatory effect, DDR1 plays a deleterious effect in kidney injury by directly regulating extracellular matrix production. We show that DDR1-null mice have reduced deposition of glomerular collagens I and IV as well as decreased proteinuria following the partial renal ablation model of kidney injury. Using mesangial cells isolated from DDR1-null mice, we show that these cells produce significantly less collagen compared to DDR1-null cells reconstituted with wild type DDR1. Moreover, mutagenesis analysis revealed that mutations in the collagen binding site or in the kinase domain significantly reduce DDR1-mediated collagen production. Finally, we provide evidence that blocking DDR1 kinase activity with an ATP-competitive small molecule inhibitor reduces collagen production. In conclusion, our studies indicate that the kinase activity of DDR1 plays a key role in DDR1-induced collagen synthesis and suggest that blocking collagen-mediated DDR1 activation may be beneficial in fibrotic diseases.
Copyright © 2016. Published by Elsevier B.V.
1 Communities
2 Members
1 Resources
19 MeSH Terms
Lysyl Oxidase-like-2 Cross-links Collagen IV of Glomerular Basement Membrane.
Añazco C, López-Jiménez AJ, Rafi M, Vega-Montoto L, Zhang MZ, Hudson BG, Vanacore RM
(2016) J Biol Chem 291: 25999-26012
MeSH Terms: Amino Acid Oxidoreductases, Animals, Collagen Type IV, Extracellular Matrix, Glomerular Basement Membrane, HEK293 Cells, Humans, Mice
Show Abstract · Added October 30, 2016
The 7S dodecamer is recognized as an important structural cross-linking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent cross-linking, the molecular mechanism by which such cross-links are formed has not been revealed. Here, we aimed to identify the enzyme(s) that cross-links the 7S dodecamer and characterize its expression in the kidney glomerulus. Pharmacological inhibition of candidate extracellular matrix enzymes revealed that lysyl oxidase activity is required for cross-linking of 7S polypeptides. Among all lysyl oxidase family members, lysyl oxidase-like-2 (LOXL2) was identified as the isoform cross-linking collagen IV in mouse embryonal PFHR-9 cells. Biochemical analyses revealed that LOXL2 readily promoted the formation of lysyl-derived cross-links in the 7S dodecamer but not in the NC1 domain. We also established that LOXL2 is the main lysyl oxidase family member present in the glomerular extracellular matrix. Altogether, we demonstrate that LOXL2 is a novel component of the molecular machinery that forms cross-linked collagen IV networks, which are essential for glomerular basement membrane stability and molecular ultrafiltration function.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
1 Resources
8 MeSH Terms
Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming.
Jones-Paris CR, Paria S, Berg T, Saus J, Bhave G, Paria BC, Hudson BG
(2017) Matrix Biol 57-58: 347-365
MeSH Terms: Animals, Basement Membrane, Collagen Type IV, Embryo Implantation, Extracellular Matrix Proteins, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Injections, Laminin, Mice, Peptide Fragments, Peroxidase, Pregnancy, Protein-Serine-Threonine Kinases, RNA, Messenger, Sesame Oil, Uterus
Show Abstract · Added October 30, 2016
Basement membranes (BMs) are specialized extracellular scaffolds that influence behaviors of cells in epithelial, endothelial, muscle, nervous, and fat tissues. Throughout development and in response to injury or disease, BMs are fine-tuned with specific protein compositions, ultrastructure, and localization. These features are modulated through implements of the BM toolkit that is comprised of collagen IV, laminin, perlecan, and nidogen. Two additional proteins, peroxidasin and Goodpasture antigen-binding protein (GPBP), have recently emerged as potential members of the toolkit. In the present study, we sought to determine whether peroxidasin and GPBP undergo dynamic regulation in the assembly of uterine tissue BMs in early pregnancy as a tractable model for dynamic adult BMs. We explored these proteins in the context of collagen IV and laminin that are known to extensively change for decidualization. Electron microscopic analyses revealed: 1) a smooth continuous layer of BM in between the epithelial and stromal layers of the preimplantation endometrium; and 2) interrupted, uneven, and progressively thickened BM within the pericellular space of the postimplantation decidua. Quantification of mRNA levels by qPCR showed changes in expression levels that were complemented by immunofluorescence localization of peroxidasin, GPBP, collagen IV, and laminin. Novel BM-associated and subcellular spatiotemporal localization patterns of the four components suggest both collective pericellular functions and distinct functions in the uterus during reprogramming for embryo implantation.
Copyright © 2016 Elsevier B.V. All rights reserved.
1 Communities
1 Members
3 Resources
18 MeSH Terms