Aggregation-prone Regions in HYPK Help It to Form Sequestration Complex for Toxic Protein Aggregates

Ghosh, Debasish Kumar (2018) Aggregation-prone Regions in HYPK Help It to Form Sequestration Complex for Toxic Protein Aggregates. Journal of Molecular Biology, 430 (7). pp. 963-986.

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Protein aggregates result from altered structural conformations and they can perturb cellular homeostasis. Prevention mechanisms, which function against protein aggregation by modulatory processes, are diverse and redundant. In this study, we have characterized Huntingtin interacting protein K (HYPK) as a global aggregation-regulatory protein. We report the mechanistic details of how HYPK's aggregation-prone regions allow it to sense and prevent other toxic protein's aggregation by forming unique annular-shaped sequestration complexes. Screenings for interacting partners of different aggregation-prone proteins identify HYPK as a global interacting partner/regulator of Huntingtin97Qexon1, α-Synuclein-A53T and Superoxide dismutase1-G93A. C-terminal hydrophobic region in HYPK makes direct contacts with aggregates to initiate the formation of sequestration complexes. HYPK acts as aggregate sensor by existing in a seeded amyloid-like state which also favors its own concentration dependent self-oligomerization. Oligomerization of HYPK leads to annular and non-fibrillar/amorphous aggregates. Two hydrophobic segments in the C-terminus of HYPK are responsible for its own aggregations. Self-association of HYPK follows seed-nucleation, in which oligomeric HYPK seeds nucleate to annular structures. Annular oligomers of HYPK fuse with each other to form amorphous aggregates. HYPK shows differential interactions with aggregation-prone and non-aggregating proteins, as it preferentially binds to aggregation-prone proteins with higher affinity than native/non-aggregating proteins. This favors the formation of HYPK's sequestration complexes both in cytosol and in ribosome. Besides having aggregation-preventive property, HYPK also reduces the cellular level of toxic proteins. In vivo, HYPK sequestration-complexes prevent the formation of toxic protein aggregates to physiologically play positive impact on cell survival and restoration of normal cell physiology.

Item Type: Article
Uncontrolled Keywords: Aggregation; Sequestration complexseeded; Amyloid-like protein; Hydrophobic patches; Cell survival
Subjects: Research > Research Center - Health Sciences
Depositing User: KMC Library
Date Deposited: 17 Apr 2019 09:30
Last Modified: 17 Apr 2019 09:30

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