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Conformational and aggregation properties of the 1–93 fragment of apolipoprotein A‐I
Author(s) -
Petrlova Jitka,
Bhattacherjee Arnab,
Boomsma Wouter,
Wallin Stefan,
Lagerstedt Jens O.,
Irbäck Anders
Publication year - 2014
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.2534
Subject(s) - circular dichroism , thioflavin , chemistry , biophysics , monomer , apolipoprotein b , point mutation , crystallography , fibril , protein structure , protein aggregation , mutation , biochemistry , biology , alzheimer's disease , gene , polymer , cholesterol , disease , medicine , organic chemistry , pathology
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.