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Ghosh, D.K. and Kumar, Abhishek and Ranjan, Akash (2018) Metastable states of HYPK-UBA domain's seeds drive the dynamics of its own aggregation. Biochimica et Biophysica Acta (BBA) - General Subjects, 1862 (12). pp. 2846-2861. ISSN 0304-4165

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Abstract

Protein aggregation is a multi-step process that requires sequential structural transitions of monomers during their incorporation into oligomers. Such process involves the formation of various intermediate stages in protein structures. Seed-nucleation mediated oligomerization is observed in many aggregation-prone proteins. Understanding of the protein seed's structural features and mechanisms of its transition-state formation are important for knowing the details of post-nucleation aggregation process. We have identified the metastable states in the seeds of the Ubiquitin associated (UBA) domain of Huntingtin Interacting Protein K (HYPK). This is studied by monitoring the events of dynamic transitions of metastable seeds to aggregates or monomers through microscopy, biophysical and computational techniques. HYPK-UBA seeds can exist in specific metastable state(s) that show transition from closed to open conformations, thereby reorienting the helix associated hydrophobic patches to cause its self-aggregation. Metastable seeds show inter-seed exchange of monomers through simultaneous dissociation-association phenomenon. Monomer release from metastable seeds can cause the dissolution of the aggregates. Like metastable monomers, metastable seeds also show reduction in their secondary structure by altering the molecular contacts and solvent accessible hydrophobic surfaces. Induction of metastable seeds from the ground-state is a slow thermodynamic process and it results from excitable perturbations. Conclusively, we propose the concept that the thermodynamic induction of metastable states in HYPK-UBA seed potentiates the molecule to switch its conformations that increases the protein's self-aggregation by the mechanism of hydrophobic patch collapse, while also releasing the monomers from oligomeric seeds due to structural instability

Item Type: Article
Uncontrolled Keywords: Prion-like protein; Metastable state; Aggregation
Depositing User: Users 2 not found.
Date Deposited: 08 Oct 2018 18:57
Last Modified: 08 Oct 2018 18:57
URI: http://cdfd.sciencecentral.in/id/eprint/867

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