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Thermodynamic Origins of Selectivity in the Interactions of N- TIMP Variants and Metalloproteinases Catalytic Domains
Title
Thermodynamic Origins of Selectivity in the Interactions of N- TIMP Variants and Metalloproteinases Catalytic Domains.
Creator
Zou, Haiyin, Brew, Keith, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Matrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue...
Show moreMatrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) which are avid broad-spectrum inhibitors of numerous human matrixins (MMPs and ADAMs). Uncontrolled matrix degradation occurs when the balance between TIMPs and MMPs is disrupted, resulting in serious diseases such as cancer, arthritis and chronic tissue ulcers. Thus, the engineering of TIMPs to produce highly selective and efficacious inhibitors of individual MMPs may be utilized for future treatment of diseases. Such engineering requires detailed analysis for the structural and biophysical information of MMP-TIMP interaction. Changes in the dynamics of proteins and solvent that accompany their associations with different binding partners, influence the specificity of binding through entropic effects. From the current studies it appears that the interactions of the inhibitory domains of TIMPs-1 and -2 (N-TIMPs) with MT1-MMP are driven by entropy increases that are partitioned between solvent and conformational entropy (ΔSsolv and ΔSconf), and a large conformational entropy penalty is responsible for the weak inhibition of MT1-MMP by NT1.We investigated how mutations that modify N-TIMP selectivity affect the thermodynamics of interactions with MMP1, MMP3 and MT1-MMP. The weak inhibition of MT1-MMP by N-TIMP-1 is enhanced by mutation of threonine 98, on the edge of the binding ridge, to leucine. This mutation increases the large ΔSconf cost for binding to MT1-MMP but this is offset by a greater increase in ΔSsolv. In contrast, this mutation enhances binding to MMP3 by increasing ΔSconf for the interaction. ΔSsolv and ΔSconf show mutual compensation for all interactions, with characteristic ranges for each MMP. Distinct electrostatic and dynamic features of MMPs are key factors in their selective inhibition.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004643
Subject Headings
Metalloproteinases -- Inhibitors., Proteolytic enzymes., Extracellular matrix proteins., Apoptosis.
Format
Document (PDF)
Topological Specificity in Inhibitor Recognition by Matrix Metalloproteinases
Title
Topological Specificity in Inhibitor Recognition by Matrix Metalloproteinases.
Creator
Lauer-Fields, Janelle, Florida Atlantic University, Brew, Keith, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Alterations in activities of one family of proteases, the metzincins have been implicated in an array of physiological and pathological processes. In the present study, metzincin inhibitors were developed by utilizing topologically constrained peptides and pseudopeptides. The endothelin-family framework was used to develop a disulfideconstrained topology. This framework was chosen due to its three-dimensional similarity with a family of endogenous metzincin inhibitors, the tissue inhibitors...
Show moreAlterations in activities of one family of proteases, the metzincins have been implicated in an array of physiological and pathological processes. In the present study, metzincin inhibitors were developed by utilizing topologically constrained peptides and pseudopeptides. The endothelin-family framework was used to develop a disulfideconstrained topology. This framework was chosen due to its three-dimensional similarity with a family of endogenous metzincin inhibitors, the tissue inhibitors of metalloproteases (TIMPs). The collagenous triple-helix was chosen as a second framework, because only a subset of proteolytic enzymes have the capacity to bind and hydrolyze a triple-helix. Both templates were successfully modified to generate an array of inhibitors. These inhibitors displayed subnanomolar to micromolar apparent Ki values, while being moderately selective metzincin inhibitors. In both cases the threedimensional structure was determined to be important for activity. This work encourages the further development of both frameworks as metzincin inhibitors.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000867
Subject Headings
Metalloproteinases--Inhibitors, Proteolytic enzymes, Extracellular matrix proteins
Format
Document (PDF)
A study of Caenorhabditis elegans tissue inhibitor of metalloproteinases
Title
A study of Caenorhabditis elegans tissue inhibitor of metalloproteinases.
Creator
Paul, Tamara., Florida Atlantic University, Brew, Keith
Abstract/Description
Tissue Inhibitors of Metalloproteinases (TIMPs) are produced by a wide variety of cell types. Similar to matrixins, the expression of TIMPs in the tissue is also controlled during tissue remodeling and physiological conditions to maintain a balance in the metabolism of extracellular matrix. Disruption of this balance can result in diseases associated with uncontrolled turnover of matrix, such as arthritis, cancer, and cardiovascular disease. Some of the biological processes TIMPs participate...
Show moreTissue Inhibitors of Metalloproteinases (TIMPs) are produced by a wide variety of cell types. Similar to matrixins, the expression of TIMPs in the tissue is also controlled during tissue remodeling and physiological conditions to maintain a balance in the metabolism of extracellular matrix. Disruption of this balance can result in diseases associated with uncontrolled turnover of matrix, such as arthritis, cancer, and cardiovascular disease. Some of the biological processes TIMPs participate in include: regulation of cell morphology and organ morphogenesis, inhibition of angiogenesis, steroidogenesis, and tissue remodeling. One major function of TIMPs is inhibition of Matrix Metaloproteinase (MMPs). This project used bioinformatic techniques to identify two Caenorhabditis elegans TIMP cDNA cloned by BLAST searching of EST database. These TIMP cDNA were amplified, cloned and expressed, proteins were purified. Kinetic studies were carried out to evaluate the inhibitory activities against various MMPs and TACE. This research project will provide some insight on the function of C. elegans TIMPs.
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Date Issued
2006
PURL
http://purl.flvc.org/fcla/dt/13414
Subject Headings
Endopeptidases--Inhibitors, Proteolytic enzymes, Extracellular matrix proteins, Metalloproteinases--Inhibitors
Format
Document (PDF)
Metalloprotease Profiling in Melanoma
Title
Metalloprotease Profiling in Melanoma.
Creator
Giricz, Orsolya, Florida Atlantic University, Fields, Gregg B., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
The proteolytic activities of the ADAM (a disintegrin and metalloproteinase), ADAMTS (a disintegrin and metalloproteinases with thrombospondin motifs) and MMP (matrix metalloproteinase) protein families play important roles in normal and multiple pathological conditions. These metalloproteases have potential implications in the degradation of the extracellular matrix and in the processing of bioactive molecules. Under pathological conditions these proteases are involved in many diverse...
Show moreThe proteolytic activities of the ADAM (a disintegrin and metalloproteinase), ADAMTS (a disintegrin and metalloproteinases with thrombospondin motifs) and MMP (matrix metalloproteinase) protein families play important roles in normal and multiple pathological conditions. These metalloproteases have potential implications in the degradation of the extracellular matrix and in the processing of bioactive molecules. Under pathological conditions these proteases are involved in many diverse processes from tumor cell migration to cartilage destruction in rheumatoid arthritis. In the present study, the gene expression levels of six ADAMs, eight MMPs, and four ADAMTSs were analyzed by Real Time PCR. RNA was isolated from multiple normal fibroblast and metastatic melanoma cell lines, as well as the isogenic normal tissue and tumor samples. This method allowed for detected changes in mRNA expressiOn of the individual metalloproteainase genes to be compared between normal and metastatic states, and also between tissue and cultured cells. Substantial differences have been observed in the level of ADAM and MMP mRNA expression between tissue and cell lines. In general, the level of expression is several folds higher in cultured cells compared to the isogenic tissue they are derived from. Protein microarrays were utilized in order to evaluate the correlations between MMP and TIMP mRNA copy numbers and protein abundance in cell culture. In several cases, distinct differences were observed regarding the localization of the proteins examined. In order to determine if the metalloprotease genes that were elevated at the level of RNA expression produce functional proteins, the foundations of an in situ FRET assay have been established. This will greatly aid in a better understanding of the behavior of metallopeptidases in a cellular context.
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Date Issued
2008
PURL
http://purl.flvc.org/fau/fd/FA00000859
Subject Headings
Tumor markers--Research, Metalloproteinases--Inhibitors, Melanoma--Research, Proteins--Synthesis, Genetic translation
Format
Document (PDF)
Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeutics
Title
Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeutics.
Creator
Nagase, Hideaki, Brew, Keith
Abstract/Description
Matrix metalloproteinases (MMPs) play a central role in many biological processes such as development, morphogenesis and wound healing, but their unbalanced activities are implicated innumerous disease processes such as arthritis, cancer metastasis, atherosclerosis, nephritis and fibrosis. One of the key mechanisms to control MMP activities is inhibition by endogenous inhibitors called tissue inhibitors of metalloproteinases (TIMPs). This review highlights the structures and inhibition...
Show moreMatrix metalloproteinases (MMPs) play a central role in many biological processes such as development, morphogenesis and wound healing, but their unbalanced activities are implicated innumerous disease processes such as arthritis, cancer metastasis, atherosclerosis, nephritis and fibrosis. One of the key mechanisms to control MMP activities is inhibition by endogenous inhibitors called tissue inhibitors of metalloproteinases (TIMPs). This review highlights the structures and inhibition mechanism of TIMPs, the biological activities of TIMPs, the unique properties of TIMP-3, and the altered specificity towards MMPs achieved by mutagenesis. A potential therapeutic use of TIMP variants is discussed.
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Date Issued
2002-04-02
PURL
http://purl.flvc.org/fcla/dt/3327266
Subject Headings
Gene Therapy --Methods, Genetic Engineering --methods, Protein Structure, Tertiary, Rheumatic Diseases --therapy, Tissue Inhibitor of Metalloproteinases, Wound Healing --physiology, Metalloproteinases --Inhibitors --Therapeutic use
Format
Document (PDF)