Proteoglycan research最新文献

{"title":"Heparanase-A single protein with multiple enzymatic and nonenzymatic functions.","authors":"Israel Vlodavsky, Yasmin Kayal, Maram Hilwi, Soaad Soboh, Ralph D Sanderson, Neta Ilan","doi":"10.1002/pgr2.6","DOIUrl":"10.1002/pgr2.6","url":null,"abstract":"<p><p>Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase-based therapy has not been implemented in the clinic. Unlike heparanase, heparanase-2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS-degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10398610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10325441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Functional and structural insights into human <i>N</i>‐deacetylase/<i>N</i>‐sulfotransferase activities”","authors":"","doi":"10.1002/pgr2.12","DOIUrl":"https://doi.org/10.1002/pgr2.12","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135857748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay of heparan sulfate chains with the core proteins of syndecans 2 and 4","authors":"Martyna Maszota‐Zieleniak, Adam Liwo, Sylvie Ricard‐Blum, Sergey A. Samsonov","doi":"10.1002/pgr2.10","DOIUrl":"https://doi.org/10.1002/pgr2.10","url":null,"abstract":"Abstract We have previously shown that the extracellular domains of the four syndecans are intrinsically disordered, and adopt a wide range of conformations. We report here the building of coarse‐grained models of the extracellular domains of human syndecans 2 and 4 using small‐angle X‐ray scattering restraints. One, two or three heparan sulfate (HS) hexadecasaccharides, (IdoA[2S]GlcNS[6S]) 8 , were attached to three serine residues of the core proteins, resulting in eight variants for each syndecan that were used for all‐atom molecular dynamics (MD) simulations (0.5–1 µs). Syndecan‐4 had a larger conformational diversity than syndecan‐2, and remained extended during MD simulations in absence of HS whereas syndecan‐2 adopted more compact conformations. Their core proteins thus appeared to be structurally distinct. The HS chains also behave differently, the middle chain being more flexible in syndecan‐4, and the third chain being able to interact with the core protein regions mediating cell adhesion. The cell adhesion sites on both core proteins were flexible, with or without HS chains, the NXIP motif of syndecan‐2 being located in a particularly flexible region. In conclusion, the HS chains induce moderate changes in the conformational dynamics of both syndecans, depending on the number of HS chains and their location on the core protein, and on the core protein itself.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136260478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfated motifs in heparan sulfate inhibit <i>Streptococcus pneumoniae</i> adhesion onto fibronectin and attenuate corneal infection.","authors":"Atsuko Hayashida, Hajirah N Saeed, Fuming Zhang, Yuefan Song, Jian Liu, William C Parks, Paulo J M Bispo, Pyong Woo Park","doi":"10.1002/pgr2.9","DOIUrl":"10.1002/pgr2.9","url":null,"abstract":"<p><p>A large number of bacterial pathogens bind to host extracellular matrix (ECM) components. For example, many Gram-negative and Gram-positive pathogens express binding proteins for fibronectin (FN) on their cell surface. Mutagenesis studies of bacterial FN-binding proteins have demonstrated their importance in pathogenesis in preclinical animal models. However, means to draw on these findings to design therapeutic approaches that specifically target FN-bacteria interactions have not been successful because bacterial pathogens can elaborate several FN-binding proteins and also because FN is an essential protein and likely a nondruggable target. Here we report that select heparan compounds potently inhibit <i>Streptococcus pneumoniae</i> infection of injured corneas in mice. Using intact heparan sulfate (HS) and heparin (HP), heparinase-digested fragments of HS, HP oligosaccharides, and chemically or chemoenzymatically modified heparan compounds, we found that inhibition of <i>S. pneumoniae</i> corneal infection by heparan compounds is not mediated by simple charge effects but by a selective sulfate group. Removal of 2-<i>O</i>-sulfates significantly inhibited the ability of HP to inhibit <i>S. pneumoniae</i> corneal infection, whereas the addition of 2-<i>O</i>-sulfates to heparosan (H) significantly increased H's ability to inhibit bacterial corneal infection. Proximity ligation assays indicated that <i>S. pneumoniae</i> attaches directly to FN fibrils in the corneal epithelial ECM and that HS and HP specifically inhibit this binding interaction in a 2-<i>O</i>-sulfate-dependent manner. These data suggest that heparan compounds containing 2-<i>O</i>-sulfate groups protect against <i>S. pneumoniae</i> corneal infection by inhibiting bacterial attachment to FN fibrils in the subepithelial ECM of injured corneas. Moreover, 2-<i>O</i>-sulfated heparan compounds significantly inhibited corneal infection in immunocompromised hosts, by a clinical keratitis isolate of <i>S. pneumoniae</i>, and also when topically administered in a therapeutic manner. These findings suggest that the administration of nonanticoagulant 2-<i>O</i>-sulfated heparan compounds may represent a plausible approach to the treatment of <i>S. pneumoniae</i> keratitis.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84998073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of hyperglycemia‐evoked intracellular hyaluronan accumulation and its activity on the autophagic and endoplasmic reticulum stress pathways","authors":"A. Wang, Aimin Wang, V. Hascall","doi":"10.1002/pgr2.7","DOIUrl":"https://doi.org/10.1002/pgr2.7","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84421742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional and structural insights into human N‐deacetylase/N‐sulfotransferase activities","authors":"Sylvain D. Vallet, T. Annaval, R. Vivès, Emeline Richard, Jérôme Hénault, C. Le Narvor, D. Bonnaffé, B. Priem, R. Wild, H. Lortat‐Jacob","doi":"10.1002/pgr2.8","DOIUrl":"https://doi.org/10.1002/pgr2.8","url":null,"abstract":"Heparan sulfate (HS) is a linear polysaccharide composed of a glucuronic acid (GlcA)‐N‐acetyl‐glucosamine (GlcNAc) disaccharide repeat motif, polymerized by the EXT1–EXT2 complex. It is extensively modified by a series of Golgi localized enzymes, that generate distinct saccharide sequences involved in the binding and the regulation of numerous protein partners. N‐deacetylase/N‐sulfotransferase (NDST), of which four isoforms have been identified in mammals, are involved in the first step of this process and catalyze both the N‐deacetylation of the GlcNAc residues into GlcNH2 and its re‐N‐sulfation into GlcNS residues. Further modifications of the HS chain depend on this first maturation event, NDST action is, therefore, key to HS biosynthesis. However, although the sulfotransferase domain of NDST1 has been characterized at the structural level some 20 years ago, information on the overall structure and activity of the enzyme are still lacking. Here, we report the characterization of the two most expressed NDSTs in humans, NDST1 and NDST2, and a model structure of NDST1 homodimer using cryoelectron microscopy combined with AlphaFold2 modeling. Structure‐driven mutagenesis along with two bioassays to follow the protein activities allowed us to characterize the kinetics of the deacetylation and sulfoaddition and to identify the residue H529 as necessary for N‐deacetylation. These results shed light on a poorly understood family of enzymes and will help deciphering the molecular basis for HS and heparin maturation.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87913298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glypicans, 35 years later","authors":"J. Filmus","doi":"10.1002/pgr2.5","DOIUrl":"https://doi.org/10.1002/pgr2.5","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85389021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional organization of extracellular hyaluronan, CD44, and RHAMM","authors":"M. Cowman, E. Turley","doi":"10.1002/pgr2.4","DOIUrl":"https://doi.org/10.1002/pgr2.4","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76612066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Optimization of Collagen-targeting Peptide-Glycosaminoglycans for Inhibition of Platelets Following Endothelial Injury.","authors":"Michael Nguyen, Tanaya Walimbe, Andrew Woolley, John Paderi, Alyssa Panitch","doi":"10.1002/pgr2.3","DOIUrl":"10.1002/pgr2.3","url":null,"abstract":"<p><p>Many endothelial complications, whether from surgical or pathological origins, can result in the denudation of the endothelial layer and the exposure of collagen. Exposure of collagen results in the activation of platelets, leading to thrombotic and inflammatory cascades that ultimately result in vessel stenosis. We have previously reported the use of peptide-GAG compounds to target exposed collagen following endothelial injury. In this paper we optimize the spacer sequence of our collagen binding peptide to increase its conjugation to GAG backbones and increase the peptide-GAG collagen binding affinity by increasing peptide C-terminal cationic charge. Furthermore, we demonstrate the use of these molecules to inhibit platelet activation through collagen blocking, as well as their localization to exposed vascular collagen following systemic delivery. Altogether, optimization of peptide sequence and linkage chemistry can allow for increased conjugation and function, having implications for glycoconjugate use in other clinical applications.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75867783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The centrality of proteoglycan research: Expect the unexpected","authors":"R. Iozzo","doi":"10.1002/pgr2.2","DOIUrl":"https://doi.org/10.1002/pgr2.2","url":null,"abstract":"","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75813250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}