Saksham Gautam & Shweta Saran*
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
Orchid Number: SS: 0000-0002-0238-498X
Received : 11th November, 2024 ; Revised : 29th December, 2024
DOI:-https://doi.org/10.5281/zenodo.15731938
Abstract– The p62/SQSTM1 (Sequestosome 1) is a conserved adaptor protein involved in various cellular pathways like selective autophagy, ubiquitin signalling, and protein homeostasis. p62 is extensively studied in higher eukaryotes, while its structural and functional roles in lower eukaryotes remain unclear. This study analyses the p62 homolog of Dictyostelium discoideum (Dd) through phylogenetic, structural, and domain interaction analysis. Cross-species evolutionary assessment revealed that Ddp62 retains key functional domains but exhibits differences in oligomerisation and ubiquitin-binding mechanisms. Using AlphaFold 3-based structural modelling and molecular docking, we accessed and compared the oligomerisation properties of the Ddp62-PB1 domain with PB1 domains of higher eukaryotic organisms (Homo sapiens, Rattus norvegicus). Results show that Ddp62-PB1 can form both homo- and heterodimers with a strong affinity than human p62. Similarly, the UBA domain of Ddp62 displayed a strong electrostatic binding affinity for ubiquitin, indicating a more rigid and specific interaction, unlike the more flexible ubiquitin recognition in higher eukaryotes. Our findings suggest that p62 functions primarily as an aggregation-prone scaffold protein in lower eukaryotes. At the same time, in higher organisms, it has evolved into a dynamic regulator of selective autophagy and cellular stress responses. This study provides insights into the functional divergence of p62, highlighting its transition from a structural autophagy adaptor to a versatile signalling hub in eukaryotic evolution.
Keywords: p62/SQSTM1, ubiquitin signalling, PB1 oligomerisation, aggregation, in silico
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