Chemical Sciences Seminars

Beta-sheet Mediated Aggregation of Polyalanine Peptides in Various Solvents

by Prof. Basak Soumen (Saha Institute of Nuclear Physics, Calcutta)

Friday, October 1, 2010 from to (Asia/Kolkata)
at Colaba Campus ( AG-66 )
TIFR, Mumbai
Description
The role of protein misfolding and aggregation in diseases, both inherited and acquired, was established over the past few decades. The inherited neuromuscular disorder OPMD (Oculopharyngeal Muscular Dystrophy) is one such example, in which patients suffer from pro-limb weakness, drooping eyelids and difficulty in swallowing. Deposits of an improperly folded RNA-binding protein, PAPB2, are found in muscle tissues and cell nuclei of individuals suffering from OPMD. Polyalanine expansions in PABP2 induce misfolding and aggregation of the protein into insoluble inclusions, leading to the disease. 

We have studied the conformational and aggregation properties of three synthesized peptides mimicking the N-terminal polyalanine segment of PABP2, having the generic sequence Ac-Lys-Met-(Ala)n-Gly-Tyr with n = 7, 11 and 17 (referred to as 7-ala, 11-ala and 17-ala, respectively). The two longer peptides (11-ala and 17-ala) were found to adopt -sheet structures on the way to forming amorphous aggregates and exhibited high toxicity to cells in culture, while 7-ala formed -helix and was benign towards the cells. A striking result was the strong tendency of the longer peptides to form well defined fibrils via the -sheet pathway, when incubated in alkaline solution (at pH > 10) or in water-alcohol mixtures. The results of these investigations will be presented and their implications discussed.
Organised by Shashikant Kadam