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 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. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection
| Identifer | oai:union.ndltd.org:fau.edu/oai:fau.digital.flvc.org:fau_33502 |
| Contributors | Zou, Haiyin (author), Brew, Keith (Thesis advisor), Florida Atlantic University (Degree grantor), Charles E. Schmidt College of Medicine, Department of Biomedical Science |
| Publisher | Florida Atlantic University |
| Source Sets | Florida Atlantic University |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation, Text |
| Format | 133 p., application/pdf |
| Rights | Copyright © is held by the author, with permission granted to Florida Atlantic University to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder., http://rightsstatements.org/vocab/InC/1.0/ |
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