Gregory I. Goldberg, Ph.D.
Professor of Dermatology and Biochemistry and Molecular Biophysics
Matrix Metalloproteases (MMPs) secreted by eucaryotic cells initiate tissue remodeling by degradation of existing ECM macromolecules such as collagens and proteoglycans. Membrane-bound enzymes of this group are involved in proteolytic activation of Gelatinase A (GelA), with other functions yet to be discovered. Malignant cells exploit these proteases to promote tumor invasion and metastasis.
Our research into biological function of MMPs is based on the hypothesis that spatially regulated extracellular proteolysis is accomplished by compartmentalization of the enzymes via their interaction with molecular structures on the cell surfaces and/or fibrils of the ECM where the physiological activation of proenzymes occurs.
Thus, mechanistic study of such interactions is a major focus of our attention. In this respect, the discovery of a cell surface activation mechanism of GelA and isolation of its membrane activator were recent breakthroughs. The regulatory C-terminal domain of GelA (GelACTD) plays a pivotal role in activation mechanism and substrate recognition. We recently have reported the crystal structure of this domain. Now, based on this structure, we have created and characterized a library of 60 single amino-acid substitution mutants that span solvent-exposed residues of this domain. These mutants will be instrumental in further investigation of the enzyme activation mechanisms. We combine biochemical, biophysical and molecular biology approaches to study the mechanisms of extracellular proteolysis by secreted and membrane-bound metalloproteases to understand the role of these enzymes in cell motility and invasion.