ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

Disassociation of beta 1-alpha 1-beta 2 from the alpha 2-alpha 3 domain of prion protein (PrP) is a prerequisite for the conformational conversion of PrPC into PrPSc: Driven by the free energy landscape

Chandrasekaran, P and Kumar, C Santosh and Rangachari, K and Sekar, K (2019) Disassociation of beta 1-alpha 1-beta 2 from the alpha 2-alpha 3 domain of prion protein (PrP) is a prerequisite for the conformational conversion of PrPC into PrPSc: Driven by the free energy landscape. In: INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, 136 . pp. 368-376.

[img] PDF
int_jou_bio_mac_136_368_2019.pdf - Published Version
Restricted to Registered users only

Download (2MB) | Request a copy
[img] Archive (ZIP)
ScienceDirect_files_19Nov2019_07-16-36.760.zip - Published Version

Download (251kB)
Official URL: https://dx.doi.org/10.1016/j.ijbiomac.2019.06.099

Abstract

Misfolding of the cellular prion protein (PrPC) into beta-sheet-rich scrapie form (PrPSC) is associated with transmissible spongiform encephalopathies. A point mutation F198S is responsible for the development of a rare inherited Gerstmann-Straussler-Scheinker disease caused by the aggregation of PrPC. Thus, identification and the structural characterization of aggregation-prone regions are essential to delineate the conversion of PrPC to the disease-associated PrPSc upon F198S mutation. In the present study, molecular dynamics simulations on the wild-type PrP (WT-PrP) and its mutant were performed to explore the structural basis responsible for aggregation driven by the mutation. Secondary structure analysis revealed that the mutant exhibited a partial unfolding on alpha 2 and the complete distortion in the 3(10)-helix of the beta 2-beta 2 loop. Remarkably, the beta 2-alpha 2 loop is in proximity to alpha 3 attributed by the long-range hydrophobic interactions and such structural intimacy is not observed in the WT-PrP. Owing to this, the beta 1-alpha 1-beta 2 regions have separated from alpha 2-alpha 3 domain resulting in the impairment on the hydrogen bond between alpha 1 and alpha 3. Thus, the present study provides a detailed structural description of the F198S mutant in line with previous experimental results and delivers insights into the structural basis responsible for the conversion of PrPC to the disease-associated PrPSc.

Item Type: Journal Article
Publication: INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Publisher: ELSEVIER
Additional Information: Copyright of this article belongs to ELSEVIER
Keywords: PrPC; PrPSc; F198S mutation; beta 2-alpha 2 loop; Molecular dynamics simulations
Department/Centre: Division of Interdisciplinary Sciences > Computational and Data Sciences
Date Deposited: 20 Nov 2019 09:53
Last Modified: 20 Nov 2019 09:53
URI: http://eprints.iisc.ac.in/id/eprint/63588

Actions (login required)

View Item View Item