Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

Jitka Petrlova; Arnab Bhattacherjee; Wouter Krogh Boomsma; Stefan Wallin; Jens O. Lagerstedt; Anders Irbäck

doi:10.1002/pro.2534

Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

Jitka Petrlova, Arnab Bhattacherjee, Wouter Krogh Boomsma, Stefan Wallin, Jens O. Lagerstedt, Anders Irbäck

14 Citations (Scopus)

Abstract

Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.

Original language	English
Journal	Protein Science
Volume	23
Issue number	11
Pages (from-to)	1559-1571
Number of pages	13
ISSN	0961-8368
DOIs	https://doi.org/10.1002/pro.2534
Publication status	Published - 1 Nov 2014
Externally published	Yes

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title = "Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I",

abstract = "Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.",

author = "Jitka Petrlova and Arnab Bhattacherjee and Boomsma, {Wouter Krogh} and Stefan Wallin and Lagerstedt, {Jens O.} and Anders Irb{\"a}ck",

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doi = "10.1002/pro.2534",

language = "English",

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T1 - Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

AU - Petrlova, Jitka

AU - Bhattacherjee, Arnab

AU - Boomsma, Wouter Krogh

AU - Wallin, Stefan

AU - Lagerstedt, Jens O.

AU - Irbäck, Anders

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.

AB - Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.

U2 - 10.1002/pro.2534

DO - 10.1002/pro.2534

M3 - Journal article

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SN - 0961-8368

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SP - 1559

EP - 1571

JO - Protein Science

JF - Protein Science

IS - 11

ER -

Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

Abstract

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