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J Phys Chem Lett. 2018 Oct 18;9(20):6060-6065. doi: 10.1021/acs.jpclett.8b02042. Epub 2018 Oct 4.

Specific Cholesterol Binding Drives Drastic Structural Alterations in Apolipoprotein A1.

Author information

1
CSIR-Institute of Genomics and Integrative Biology , South Campus, Mathura Road , New Delhi 110 025 , India.
2
Academy of Scientific and Innovative Research (AcSIR) , CSIR- Institute of Genomics and Integrative Biology , Mathura Road Campus , New Delhi 110025 , India.
3
Interdisciplinary Center for Scientific Computing , University of Heidelberg , Im Neuenheimer Feld 205 , 69120 Heidelberg , Germany.

Abstract

Proteins typically adopt a multitude of flexible and rapidly interconverting conformers, many of which are governed by specific protein interaction domains. Whereas disc-shaped oligomeric HDL and its major protein component ApoA1 have been the focus of several investigations, the structural properties of monomeric ApoA1 remain poorly understood. Using tens of independent molecular simulations (>50 μs), we reveal that ApoA1 adopts a compact conformation. Upon the addition of a physiological concentration of cholesterol to ApoA1, the monomeric protein spontaneously formed a circular conformation. Remarkably, these drastic structural perturbations are driven by a specific cholesterol binding site at the C-terminal and a novel cholesterol binding site at the N-terminal. We propose a mechanism whereby ApoA1 opens in a stagewise manner and mutating the N-terminal binding site destroys the open "belt-shaped" topology. Complementary experiments confirm that the structural changes are induced by specific association of cholesterol with ApoA1, not by the nonspecific hydrophobic effect.

PMID:
30256643
DOI:
10.1021/acs.jpclett.8b02042
[Indexed for MEDLINE]

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