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Chemistry Seminar Series 291 (10/27/17)

Date: 
October 27, 2017 - 3:00pm

Melanie Cocco, Ph.D., University of California, Irvine

Abstract:

Structural studies of proteins peripherally associated with cell membranes are difficult because the environment consists of both aqueous and lipid phases. In some cases, detergent micelles and detergent/lipid bicelles can mimic the anisotropy of cell membranes and provide an environment suitable to fold a membrane-associated protein. Here I will present a strategy to determine peripherally associated membrane protein structures including the structural studies on the neuronal growth inhibitor described below. 

Compelling evidence indicates that repair of damage to the central nervous system ( CNS) is inhibited by the presence of protein factors within myelin that prevent axonal regrowth. Myelin growth inhibitors and their common receptor have been identified as targets in the treatment of spinal cord injury and stroke. We have recently determined the NMR structure of one of the myelin growth inhibitors, the neurite outgrowth inhibitor (Nogo). We studied the structure of this protein alone and in the presence of dodecylphosphocholine micelles to mimic the natural cell membrane environment. Using several paramagnetic probes, we have defined portions of the growth inhibitor that are accessible to solvent (and consequently the Nogo receptor). Mutagenesis probed through phage-display confirms that the positions predicted to be extra-cellular are sensitive to receptor binding. Using computational docking methods, NMR data and mutagenesis results, we calculated the optimal protein-protein interface between our structure of Nogo and the Nogo receptor. With these data we predict that residues (28-58) are available to bind the Nogo receptor which is entirely consistent with functional assays. Moreover, the conformations and relative positions of side chains recognized by the receptor are now defined and may be useful in antagonist design. 
 
In addition, I will highlight our recent work in developing vaccines based on membrane protein formulations.
 

Contact Information

Name: 
Andy LiWang
Title: 
Professor
Address: 
5200 North Lake Rd.
Merced, CA 95343
United States
Address: 
5200 North Lake Rd.
Merced, CA 95343
United States