Biochemical Society Symposia最新文献_第10页

Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors. 设计选择性金属蛋白酶抑制剂TIMP(组织金属蛋白酶抑制剂)变异。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700201

Hideaki Nagase, Keith Brew

{"title":"Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors.","authors":"Hideaki Nagase, Keith Brew","doi":"10.1042/bss0700201","DOIUrl":"https://doi.org/10.1042/bss0700201","url":null,"abstract":"The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"201-12"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24052379","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}

引用次数: 85

Meprin proteolytic complexes at the cell surface and in extracellular spaces. 细胞表面和细胞外空间的蛋白水解复合物。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700053

James P Villa, Greg P Bertenshaw, John E Bylander, Judith S Bond

{"title":"Meprin proteolytic complexes at the cell surface and in extracellular spaces.","authors":"James P Villa, Greg P Bertenshaw, John E Bylander, Judith S Bond","doi":"10.1042/bss0700053","DOIUrl":"https://doi.org/10.1042/bss0700053","url":null,"abstract":"Meprins are metalloproteinases of the astacin family and metzincin superfamily that are composed of evolutionarily related alpha and beta subunits, which exist as homo- and hetero-oligomeric complexes. These complexes are abundant at the brush border membranes of kidney proximal tubule cells and epithelial cells of the intestine, and are also expressed in certain leucocytes and cancer cells. Meprins cleave bioactive peptides such as gastrin, cholecystokinin and parathyroid hormone, cytokines such as osteopontin and monocyte chemotactic peptide-1, as well as proteins such as gelatin, collagen IV, fibronectin and casein. Database predictions and initial data indicate that meprins are also capable of shedding proteins, including itself, from the cell surface. Membrane-bound meprin subunits are composed of dimeric meprin beta subunits or tetrameric hetero-oligomeric alpha beta complexes of approx. 200-400 kDa, and can be activated at the cell surface; secreted forms of homo-oligomeric meprin alpha are zymogens that form high-molecular-mass complexes of 1-6 MDa. These are among the largest extracellular proteases identified thus far. The latent (self-associating) homo-oligomeric complexes can move through extracellular spaces in a non-destructive manner, and deliver a concentrated form of the metalloproteinase to sites that have activating proteases, such as sites of inflammation, infection or cancerous growth. Meprins provide examples of novel ways of concentrating proteolytic activity at the cell surface and in the extracellular milieu, which may be critical to proteolytic function.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"53-63"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24051829","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}

引用次数: 36

Proteolysis of the collagen fibril in osteoarthritis. 骨性关节炎中胶原纤维的蛋白水解。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700115

A Robin Poole, Fred Nelson, Leif Dahlberg, Elena Tchetina, Masahiko Kobayashi, Tadashi Yasuda, Sheila Laverty, Ginette Squires, Toshihisa Kojima, William Wu, R Clark Billinghurst

{"title":"Proteolysis of the collagen fibril in osteoarthritis.","authors":"A Robin Poole, Fred Nelson, Leif Dahlberg, Elena Tchetina, Masahiko Kobayashi, Tadashi Yasuda, Sheila Laverty, Ginette Squires, Toshihisa Kojima, William Wu, R Clark Billinghurst","doi":"10.1042/bss0700115","DOIUrl":"https://doi.org/10.1042/bss0700115","url":null,"abstract":"The development of cartilage pathology in osteoarthritis involves excessive damage to the collagen fibrillar network, which appears to be mediated primarily by the chondrocyte-generated cytokines interleukin-1 and tumour necrosis factor alpha and the collagenases matrix metalloproteinase-1 (MMP-1) and MMP-13. The damage to matrix caused by these and other MMPs can result in the production of sufficient degradation products that can themselves elicit further degradation, leading to chondrocyte differentiation and eventually matrix mineralization and cell death. Knowledge of these MMPs, cellular receptors and cytokine pathways, and the ability to selectively antagonize them by selective blockade of function, may provide valuable therapeutic opportunities in the treatment of osteoarthritis and other joint diseases involving cartilage resorption, such as rheumatoid arthritis. The ability to detect the products of these degradative events released into body fluids of patients may enable us to monitor disease activity, predict disease progression and determine more rapidly the efficacy of new therapeutic agents.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"115-23"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24051834","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}

引用次数: 105

Papain-like lysosomal cysteine proteases and their inhibitors: drug discovery targets? 木瓜样溶酶体半胱氨酸蛋白酶及其抑制剂:药物发现靶点?

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700015

Dŭsan Turk, Boris Turk, Vito Turk

{"title":"Papain-like lysosomal cysteine proteases and their inhibitors: drug discovery targets?","authors":"Dŭsan Turk, Boris Turk, Vito Turk","doi":"10.1042/bss0700015","DOIUrl":"https://doi.org/10.1042/bss0700015","url":null,"abstract":"Papain-like lysosomal cysteine proteases are processive and digestive enzymes that are expressed in organisms from bacteria to humans. Increasing knowledge about the physiological and pathological roles of cysteine proteases is bringing them into the focus of drug discovery research. These proteases have rather short active-site clefts, comprising three well defined substrate-binding subsites (S2, S1 and S1') and additional broad binding areas (S4, S3, S2' and S3'). The geometry of the active site distinguishes cysteine proteases from other protease classes, such as serine and aspartic proteases, which have six and eight substrate-binding sites respectively. Exopeptidases (cathepsins B, C, H and X), in contrast with endopeptidases (such as cathepsins L, S, V and F), possess structural features that facilitate the binding of N- and C-terminal groups of substrates into the active-site cleft. Other than a clear preference for free chain termini in the case of exopeptidases, the substrate-binding sites exhibit no strict specificities. Instead, their subsite preferences arise more from the specific exclusion of substrate types. This presents a challenge for the design of inhibitors to target a specific cathepsin: only the cumulative effect of an assembly of inhibitor fragments will bring the desired result.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"15-30"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24051980","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}

引用次数: 43

Caspase activation. 半胱天冬酶激活。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700233

Kelly M Boatright, Guy S Salvesen

引用次数: 0

Substrate specificity and inducibility of TACE (tumour necrosis factor alpha-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity. 底物特异性和TACE(肿瘤坏死因子α转换酶)的诱导性:Ala-Val偏好和诱导的内在活性。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700039

Roy A Black, John R Doedens, Rajeev Mahimkar, Richard Johnson, Lin Guo, Alison Wallace, Duke Virca, June Eisenman, Jennifer Slack, Beverly Castner, Susan W Sunnarborg, David C Lee, Rebecca Cowling, Guixian Jin, Keith Charrier, Jacques J Peschon, Ray Paxton

{"title":"Substrate specificity and inducibility of TACE (tumour necrosis factor alpha-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity.","authors":"Roy A Black, John R Doedens, Rajeev Mahimkar, Richard Johnson, Lin Guo, Alison Wallace, Duke Virca, June Eisenman, Jennifer Slack, Beverly Castner, Susan W Sunnarborg, David C Lee, Rebecca Cowling, Guixian Jin, Keith Charrier, Jacques J Peschon, Ray Paxton","doi":"10.1042/bss0700039","DOIUrl":"https://doi.org/10.1042/bss0700039","url":null,"abstract":"Tumour necrosis factor alpha (TNF alpha)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor alpha, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"39-52"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24051828","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}

引用次数: 81

Structural basis of matrix metalloproteinase function. 基质金属蛋白酶功能的结构基础。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700001

Wolfram Bode

引用次数: 50

How serpins change their fold for better and for worse. 蛇是如何变好变坏的。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700163

Robin W Carrell, James A Huntington

{"title":"How serpins change their fold for better and for worse.","authors":"Robin W Carrell, James A Huntington","doi":"10.1042/bss0700163","DOIUrl":"https://doi.org/10.1042/bss0700163","url":null,"abstract":"The serpins differ from the many other families of serine protease inhibitors in that they undergo a profound change in topology in order to entrap their target protease in an irreversible complex. The solving of the structure of this complex has now provided a video depiction of the changes involved. Cleavage of the exposed reactive centre of the serpin triggers an opening of the five-stranded A-sheet of the molecule, with insertion of the cleaved reactive loop as an additional strand in the centre of the sheet. The drastic displacement of the acyl-linked protease grossly disrupts its active site and gives an overall loss of 40% of ordered structure. This ability to provide effectively irreversible inhibition explains the selection of the serpins to control the proteolytic cascades of higher organisms. The conformational mechanism provides another advantage in its potential to modulate activity. Sequential crystallographic structures now provide clear depictions of the way antithrombin is activated on binding to the heparans of the microcirculation, and how evolution has utilized this mobile mechanism for subtle variations in activity. The complexity of these modulatory mechanisms is exemplified by heparin cofactor II, where the change in fold is seen to trigger multiple allosteric effects. The downside of the mobile mechanism of the serpins is their vulnerability to aberrant intermolecular beta-linkages, resulting in various disorders from cirrhosis to thrombosis. These provide a well defined structural prototype for the new entity of the conformational diseases, including the common dementias, as confirmed by the recent identification of the familial neuroserpin dementias.","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"163-78"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24052377","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}

引用次数: 26

A tribute to Alan J. Barrett. 向艾伦·j·巴雷特致敬。

Biochemical Society Symposia Pub Date : 2003-01-01

Jeremy Saklatvala, Hideaki Nagase, Guy Salvesen

引用次数: 0

Cathepsin B and its role(s) in cancer progression. 组织蛋白酶B及其在癌症进展中的作用。

Biochemical Society Symposia Pub Date : 2003-01-01 DOI: 10.1042/bss0700263

Izabela Podgorski, Bonnie F Sloane

{"title":"Cathepsin B and its role(s) in cancer progression.","authors":"Izabela Podgorski, Bonnie F Sloane","doi":"10.1042/bss0700263","DOIUrl":"https://doi.org/10.1042/bss0700263","url":null,"abstract":"Experimental and clinical evidence has linked cathepsin B with tumour invasion and metastasis. Cathepsin B expression is increased in many human cancers at the mRNA, protein and activity levels. In addition, cathepsin B is frequently overexpressed in premalignant lesions, an observation that associates this protease with local invasive stages of cancer. Increased expression of cathepsin B in primary cancers, and especially in preneoplastic lesions, suggests that this enzyme might have pro-apoptotic features. Expression of cathepsin B is regulated at many different levels, from gene amplification, use of alternative promoters, increased transcription and alternative splicing, to increased stability and translatability of transcripts. During the transition to malignancy, a change in the localization of cathepsin B occurs, as demonstrated by the presence of cathepsin B-containing vesicles at the cell periphery and at the basal pole of polarized cells. Due to increased expression of cathepsin B and changes in intracellular trafficking, increased secretion of procathepsin B from tumours is observed. Active cathepsin B is also secreted from tumours, a mechanism likely to be facilitated by lysosomal exocytosis or extracellular processing by surface activators. Cathepsin B is localized to caveolae on the tumour surface, where binding to the annexin II heterotetramer occurs. Activation of cathepsin B on the cell surface leads to the regulation of downstream proteolytic cascade(s).","PeriodicalId":55383,"journal":{"name":"Biochemical Society Symposia","volume":" 70","pages":"263-76"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1042/bss0700263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24051671","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}

引用次数: 195