A Sulfilimine Bond Identified in Collagen IV

Vanacore, Roberto M.; Ham, Amy-Joan L.; Voehler, Markus; Sanders, Charles R.; Conrads, Thomas P.; Veenstra, Timothy D.; Sharpless, K. Barry; Dawson, Philip E.; Hudson, Billy G.

doi:10.1126/science.1176811

Cited by 225 publications

(215 citation statements)

References 33 publications

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“…Assembly of the collagen IV network is a complex process, where crosslinking of collagen IV protomers leads to the formation of a scaffold that interacts with other basement membrane proteins. A recently identified mechanism of collagen IV crosslinking is the formation of sulfilimine links between interfacing NC1 domains, a coupling mechanism which has been identified only in collagen IV so far (12).…”

Section: Discussionmentioning

confidence: 99%

“…Coupling of the NC1 domains occurs through sulfilimine bonds that were only recently recognized in living organisms (12). While vast amount of data have been collected about the structure and enzymatic activity of other members of the animal heme peroxidase family (13), we know very little about the PXDN protein and the mechanism of collagen IV crosslinking.…”

Section: Introductionmentioning

confidence: 99%

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Structure–function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking

Lázár

Péterfi

Sirokmány

et al. 2015

Free Radical Biology and Medicine

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Basement membranes provide structural support and convey regulatory signals to cells in diverse tissues. Assembly of collagen IV into a sheet-like network is a fundamental mechanism during the formation of basement membranes. Peroxidasin (PXDN) was recently described to catalyze crosslinking of collagen IV through the formation of sulfilimine bonds.Despite the significance of this pathway in tissue genesis, our understanding of PXDN function is far from complete. In this work we demonstrate that collagen IV crosslinking is a physiological function of mammalian PXDN. Moreover, we carried out structure-function analysis of PXDN to get a better insight into its role in collagen IV synthesis. We identify conserved cysteines in PXDN which mediate the oligomerization of the protein into a trimeric complex. We also demonstrate that oligomerization is not an absolute requirement for enzymatic activity but optimal collagen IV coupling is only catalyzed by the PXDN trimers.Localization experiments of different PXDN mutants in two different cell models revealed that PXDN oligomers, but not monomers, adhere on cell-surface in "hot spots", which represent previously unknown locations of collagen IV crosslinking.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure–function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking

Lázár

Péterfi

Sirokmány

et al. 2015

Free Radical Biology and Medicine

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“…Two major immunodominant regions, E A and E B , have been mapped to residues 17-31 and 127-141 of the a3(IV)NC1 (7). Further studies define them as conformational epitopes that are sequestrated in the quaternary structure of GBM dependent on a critical sulfilimine bond (8,9).…”

Section: Introductionmentioning

confidence: 99%

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

Jia

Cui²,

Yang³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Linear epitopes on the Goodpasture autoantigen involved in human anti-glomerular basement membrane (GBM) disease are not fully defined. This study investigated the linear epitopes recognized by circulating antibodies in anti-GBM patients, aiming to identify the potential nephrogenic linear epitopes and their clinical significance.Design, setting, participants, & measurements Sixty-eight patients with anti-GBM disease were enrolled. Twentyfour overlapping linear peptides were synthesized across the whole sequence of the human Goodpasture autoantigen. ELISA detected circulating antibodies against linear epitopes. Their associations with clinical features were further analyzed.Results Antibodies against linear peptides were detected in sera from 55 patients (80.9%). Three major epitopes with high frequencies were identified: P14 (41%), P16 (36.8%), and P18 (57%). P14, a formerly defined T cell epitope, was a mutual B cell epitope. Antibodies against P14 were frequently detected in patients with positive antineutrophil cytoplasmic antibodies (39.3% versus 12.5%; P=0.01). Patients with anti-P16 antibodies presented with higher serum creatinine on diagnosis (665.56227.2 versus 443.76296.8 mmol/L; P=0.001) and worse renal outcome during follow-up (hazard ratio, 2.10; 95% confidence interval, 1.10-3.90; P=0.02). The level of anti-P18 antibodies positively correlated with the percentage of crescents in glomeruli (r=0.54; P=0.008). Recognition of P22 was an independent predictor for patient death (hazard ratio, 3.02; 95% confidence interval, 1.20-7.57; P=0.02).Conclusions Antibodies against linear epitopes on the Goodpasture autoantigen could be detected in human anti-GBM disease and were associated with kidney injury. P14 was a mutual T and B cell epitope, implying its nephrogenic role in disease initiation.

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“…Collagen IV ␣ chains form triple helical protomers that self-assemble into a mesh-like network with end-to-end C-terminal associations known as NC1 hexamers. Sulfilimine (SAN) bonds between opposing methionine and lysine residues bridge the trimer-timer interface of the NC1 hexamer and thereby structurally reinforce the collagen IV network (3). The enzyme peroxidasin (Pxdn), a basement membrane-associated heme peroxidase, catalyzes the formation of sulfilimine crosslinks, a process critical for BM and tissue integrity (4).…”

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confidence: 99%

Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV

Colon

Bhave

2016

Journal of Biological Chemistry

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Edited by Amanda FosangThe basement membrane (BM) is a form of extracellular matrix that underlies cell layers in nearly all animal tissues. Type IV collagen, a major constituent of BMs, is critical for tissue development and architecture. The enzyme peroxidasin (Pxdn), an extracellular matrix-associated protein, catalyzes the formation of structurally reinforcing sulfilimine cross-links within the collagen IV network, an event essential to basement membrane integrity. Although the catalytic function of Pxdn is known, the regulation of its activity remains unclear. In this work we show through N-terminal sequencing, pharmacologic studies, and mutational analysis that proprotein convertases (PCs) proteolytically process human Pxdn at Arg-1336, a location relatively close to its C terminus. PC processing enhances the enzymatic activity of Pxdn and facilitates the formation of sulfilimine cross-links in collagen IV. Thus, PC processing of Pxdn is a key regulatory step that contributes to its function and, therefore, supports BM integrity and homeostasis.

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A Sulfilimine Bond Identified in Collagen IV

Cited by 225 publications

References 33 publications

Structure–function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking

Structure–function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV

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