Affiliations: Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India
Correspondence:
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Correspondence to: Pravir Kumar, PhD, Professor and Dean, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), Room # FW4TF3, Mechanical Engineering Building, Shahbad Daulatpur, Bawana Road, Delhi 110042, India. Tel.: +91 9818898622; E-mail: pravirkumar@dtu.ac.in; kpravir@gmail.com
Abstract: Intracellular accumulation of aggregated amyloid-β, misfolded and non-functional proteinopathy, is the hallmark feature in Alzheimer’s disease (AD). There are several mechanisms to clear the amyloid burden in a cell, including transcytosis across the blood-brain barrier, immune mediated, lysosomal pathway associated autophagy, enzymatic degradation by insulin degrading enzyme/neprilysin, and the proteasomal pathway. Among them, the ubiquitin proteasome system (UPS) is playing a critical role to prevent the intracellular amyloid-β deposition and to clear off the cellular burden in association with ubiquitin E3 ligase enzymes in AD. For ubiquitination, lysine moiety in a protein acts like a docking site for the attachment of ubiquitin molecule and different lysine residues act differently in this reaction. Therefore, it is pertinent to understand and link the role of various lysine residues along with their effector molecules, for instance, E3 ligases PARK2 and STUB1 in the ubiquitination cascade. Herein, we 1) modeled the structure of AβPP and determined its topologies and studied the impact of lysine residues in AβPP stability, 2) reported K351 as the most promising target for AβPP ubiquitination, 3) investigated the plausible role of lysine residues in non-covalent interactions mediated ubiquitin positioning in the ubiquitination, 4) detected conserved amino acids that is crucial for AβPP ubiquitination, and 5) identified the key ubiquitination enzymes and their interaction network playing major role in the ubiquitination of AβPP.
Keywords: Amyloid-β, amyloid-β protein precursor, lysine, neurodegeneration, therapeutics, ubiquitination
