Motivation

The major components of neuritic plaques found in Alzheimer disease (AD) are
peptides known as amyloid beta-peptides (Aβ), which are derived from the
proteolytic cleavage of the amyloid precursor protein (APP). In vitro Aβ may undergo
a conformational transition from a soluble form to aggregated, fibrillary beta-sheet
structures, which seem to be neurotoxic. Alternatively, it has been suggested that an
alpha-helical form can be involved in a process of membrane poration, which would
then trigger cellular death.

Aβ peptides are generated as cleavage products 39 to 43 amino acids in length from

the membrane protein, APP by two proteases, β-secretase and γ-secretase . While
only a small amount is processed by β-Secretase, also known as BACE1 (β-secretase
APP cleaving enzyme) or memapsin, APP is predominantly processed by α-Secretase,
producing a 83-amino acid C-terminal fragment, C83. Subsequent cleavage of C83 by
γ-secretase produces a non-toxic N-terminal 3kD protein.

Aβ peptides are amphiphilic with a hydrophilic N-terminal domain (residues 1 to 28)

and a hydrophobic C-terminal (residues 29 to 40-42), the latter corresponding to a
part of the transmembrane domain of APP. Aβ assembly into fibrils is initiated by a
conformational transition from random coil to β-sheet (hence the name β-amyloid)
and a nucleation-dependent aggregation process. The presence of excess amount of
Aβ deposits and neurofibrillary tangles, NFTs , comprising of hyperphosphorylated
Tau proteins are the hallmarks of an AD brain .

Phospholipase A2 (PLA2) is a small lipolytic enzyme that releases fatty acids from the
second carbon group of glycerol. It is involved in a number of physiologically
important cellular processes, such as the liberation of arachidonic acid from
membrane phospholipids. It plays a pivotal role in the biosynthesis of prostaglandin
and other mediators of inflammation. PLA2 has four to seven disulphide bonds and
binds a calcium ion that is essential for activity. Within the active enzyme, the alpha
amino group is involved in a conserved hydrogen-bonding network linking the N-
terminal region to the active site. There are ample evidences supporting both the
upregulation as well as down regulation of AD by PLA2. The study of Interaction
between these two proteins will contribute significantly for the better understanding
of the cause of AD and its therapy.

Abstract Gaurav Bhadauria

Goal
Proteins play an essential role in nearly all cell functions such as composing cellular
structure and promoting chemical reactions. The multiplicity of functions that
proteins execute in most cellular processes and biochemical events is attributed to
their interactions with other proteins. It is thus critical to understand protein–protein
interactions (PPIs) for getting a complete holistic view of the biological system.
Domains are the building blocks of proteins; therefore, proteins are assumed to
interact as a result of their interacting domains.

In my study I will try to infer direct structural interactions for interacting protein pair
and will try to establish a correlation between them.

Abstract Gaurav Bhadauria