期刊
PROTEIN SCIENCE
卷 23, 期 11, 页码 1559-1571出版社
WILEY-BLACKWELL
DOI: 10.1002/pro.2534
关键词
disordered protein; amyloidogenic mutations; secondary-structure probability; fibril formation; molecular simulation
资金
- Swedish Research Council [K2014-54X-22426-01-3]
- Royal Physiographic Society in Lund
- Greta and Johan Kocks Foundation
- Gyllenstierna Krapperup's Foundation
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 -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.
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