COMPUTER AIDED PROTEIN STRUCTURE PREDICTION OF THE GAMMA SECRETASE USING MODELLER

Abstract

ABSTRACT Gamma-secretase is a multi-subunit protease complex, an integral membrane protein that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. The most substrates of gamma-secretase are APP, a large integral membrane protein that, when cleaved by both gamma and beta-secretase, produces a short 39-42 amino acid peptide called amyloid-beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease (AD) patients.The gamma-secretase complex consists of four individual proteins: presenilin, PEN-2 (presenilin enhancer-2), APH-1 (anterior pharynx-defective-1), nicastrin. We know the structure of two subunits presenilin and nicastrin, but two other subunit’s (APH-1 and PEN-2) structures are still unknown. Our purpose is ‘to predict the structure of sub units of gamma-secretase and use this structure to predict the complex structure of the gamma-secretase’. The amino acid sequence of gamma-secretase two subunits; PEN-2 and APH-1 are searched in the NCBI database. Tertiary structures, as well as quaternary structures of proteins predicted by MODELLER and five models of PEN-2 and APH-1 subunits were generated. After the structure validation of those two subunits by Ramachandran plot, based on highest number of residue in the favoured region and allowed region, both subunits are selected for docking. Docking of all four subunits (presenilin, APH-1, PEN-2, nicastrin) are done and finally predicted the complex structure of all of the subunits of gamma secretase. The energy was found to be -560.86 KJ. The tertiary structure of the gamma-secretase enzyme is being predicted with the most number of residues in the favoured region in Ramachandran plot. The residue in the favoured region and the allowed regions are found to be 91.40 % and 6.0 % of the total residues respectively. This indicates a good interaction of subunit structures to form the complex structure of gamma- secretase enzyme.