Ghosh, D.K. and Roy, Ajit and Ranjan, Akash (2018) Disordered nanostructure in Huntingtin interacting protein K acts as stabilizing switch to prevent protein aggregation. Biochemistry, 57 (13). pp. 2009-2023. ISSN 0006-2960

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Abstract

Protein misfolding due to mutation(s) and/or generation of unstable intermediate state(s) can be the cause of aberrant aggregations, leading to cellular degeneration. While molecular signatures like amyloidogenic regions cause aggregation, other features in proteins, like disorder and unique complexity regions, regulate and restrict such adhesive accumulation processes. Huntingtin interacting protein K (HYPK) is an aggregation-prone protein. Using various biophysical, microscopy and computational techniques, we have deciphered how HYPK’s N-terminal nano-disordered region plays a significant modulatory role in preventing its own and other protein’s aggregation. HYPK’s C-terminal hydrophobic regions lead to annular oligomerization and inter-molecular charge-interactions among the residues of low complexity region (LCR) generate amorphous aggregates. The N-terminal disordered nanostructure loops towards the C-terminus and a negative charge-rich patch in this region interacts with the LCR to shield LCR’s positive charges. This interaction is required to prevent HYPK aggregation. Loss of this interaction causes partial unfolding of the structured C-terminus, resulting in HYPK’s molten globule-like state and rapid annular oligomerization. The N-terminus also determines the specificity to mediate the differential bindings with aggregation-prone and wild-type Huntingtin-exon1 proteins (Huntingtin97Qexon1 and Huntingtin25Qexon1). A sliding interaction of the specific N-terminal segment of HYPK along the extended poly-glutamine region of Huntingtin-exon1 is responsible for HYPK’s stronger affinity towards aggregation-prone Huntingtin compared to its non-aggregating counterpart. Overall, our study provides evidence for the existence of disordered nanostructure in HYPK protein that mechanistically plays a decisive role in preventing both self and non-self protein aggregation.

Item Type:	Article
Depositing User:	Users 2 not found.
Date Deposited:	09 Feb 2018 10:08
Last Modified:	09 Apr 2018 20:43
URI:	http://cdfd.sciencecentral.in/id/eprint/823

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