Thursday, July 22, 11 AM
Bldg. 38A, 5th floor conference room

         Neeti Sinha
         Laboratory of Experimental and Computational Biology
         NCI-FCRDC.


	Protein Misfolding and Amyloidogenic Diseases
	_____________________________________________


The structural analysis of the amyloidogenic proteins will help us both to
understand the general features and characteristics which predispose them
for the conformational alteration and, on the other hand, will give us an
insight towards the cure of several neurodegenerative and other
amyloidogenic diseases. Amyloidogenic proteins have an inherent capacity
to self assemble into a fibril like structure, known as amyloid. The
assembly is in such a way that the beta-sheets are stacked around the
fibre axis, where the beta-strands lie perpendicular to the fibre axis.
The tertiary structures of all the native amyloidogenic proteins are very
different from each other. However, all amyloid fibrils have a basic
structure similar to each other. This suggests that either these proteins
undergo a conformational change, resulting in overall similar
conformations forming such amyloids, or alternatively, a characteristic
sub-structural motif is a critical component in the formation of the
amyloid. Experimental evidence suggests the second possibility as more
likely. We are in the process of structurally defining amyloidogenic
proteins. Based on the architecture and structural parameters we have
detected recurring motif occuring in all available native structures of
amyloidogenic proteins.

This motif is proposed to participate in amyloid formation by flipping
from the monomer, and domain swapping with a previous such structure in
the growing amyloid fiber. We are constructing a consistent model for
amyloid formation. Our goal is to Identify the structural determinants
predisposing a protein to such a conformational change, and predict likely
candidate proteins, or their mutational variants.

-- 
Eugene V. Koonin, PhD
National Center for Biotechnology Information
National Library of Medicine
National Institutes of Health, Bldg. 38A, Rm. 5N505A (5th floor)
Bethesda, MD 20894, USA
Voice: (301)435-5913
Fax: (301)480-9241
email koonin@ncbi.nlm.nih.gov