From bacteria to humans, essential molecular signals control multiple aspects of cellular behavior. Recently, a universal signaling paradigm, termed regulated intramembrane proteolysis, (RIP) has been discovered. In RIP, membrane proteins are cleaved in their intramembrane regions resulting in water-soluble signals. These signals relocate within the cell or to the extracellular media and act as modulators of cell metabolism and development. The intramembrane cutting enzymes constitute a novel class of integral membrane proteins. The goal of this research is to unravel the molecular mechanisms underlying RIP by focusing on a ubiquitous intramembrane protease family called Rhomboids. The work will be divided in three fronts: (I) biochemical study of the factors that regulate Rhomboid intramembrane protease activity; (II) identification of the features that distinguish good substrates from bad ones and determine the precise location of the cleavage site; and (III) elucidation of the three-dimensional structure of Rhomboid to allow interpretation of functional data in structural terms. To achieve these goals, biochemical and biophysical approaches will be used in combination with structural techniques such as high-resolution electron-cryo microscopy, nuclear magnetic resonance and X-ray crystallography.
Broader impact: The City College of New York has a substantial proportion of underrepresented minority and new immigrant students. The outlined multidisciplinary research will draw and train graduate and undergraduate students from the general areas of biology, chemistry and physics with a drive to understand biological processes in detail. These students will gain experience in membrane protein research and be trained in the principles and applications of modern structural biology in general, and of electron cryo-microscopy in particular. A graduate course in electron cryo-microscopy of macromolecular assemblies will be developed and offered every year, under the leadership of the New York Structural Biology Center, and open to the New York City graduate student community.
|Effective start/end date||1/09/08 → 31/03/11|
- National Science Foundation: $868,684.00