An In-Silico Investigation of Key Lysine Residues and Their Selection for Clearing off Aβ and Holo-AβPP Through Ubiquitination
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Malicious progression of neurodegeneration is a consequence of toxic aggregates of proteins or peptides such as amyloid beta (Aβ) reported in Alzheimer’s disease (AD). These aggregates hinder the electrochemical transmission at neuronal junctions and thus deteriorate neuronal-health by triggering dementia. Electrostatic and hydrophobic interactions among amino-acid residues are the governing principle behind the self-assembly of aforesaid noxious oligomers or agglomerate. Interestingly, lysine residues are crucial for these interactions and for facilitating the clearance of toxic metabolites through the ubiquitination process. The mechanisms behind lysine selectivity and modifications of target proteins are very intriguing process and an avenue to explore the clearance of unwanted proteins from neurons. Therefore, it is fascinating for the researchers to investigate the role of key lysine, their selectivity and interactions with other amino acids to clear-off toxic products in exempting the progression of Neurodegenerative disorders (NDDs). Herein, (1) we identified the aggregation prone sequence in Aβ40 and Aβ42 as ‘HHQKLVFFAE’ and ‘SGYEVHHQKLVFFAEDVG/KGAIIGLMVGGV’ respectively with critical lysine (K) at 16 and 28 for stabilizing the aggregates; (2) elucidated the interaction pattern of AβPP with other Alzheimer’s related proteins BACE1, APOE, SNCA, APBB1, CASP8, NAE1, ADAM10, and PSEN1 to describe the pathophysiology; (3) found APOE as commonly interacting factor between amyloid beta and Tau for governing AD pathogenesis; (4) reported K224, K351, K363, K377, K601, K662, K751, and K763 as potential putative lysine for facilitating AβPP clearance through ubiquitination thereby arresting Aβ formation; and (5) observed conserved glutamine (Q), glutamic acid (E), and alpha-helical conformation as few crucial factors for lysine selectivity in the ubiquitination of AβPP.
KeywordsAmyloid beta (Aβ) Amyloid-beta precursor protein (AβPP) Alzheimer’s disease (AD) Lysine (K) Ubiquitin proteasome system (UPS) Neurodegeneration
We would like to thanks the senior management of Delhi Technological University for constant support and encouragement.
Compliance with Ethical Standards
Conflict of interest
There is no conflict or competing interest declared by the authors.
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