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

Authors

  • Jitka Petrlova,

    1. Department of Experimental Medical Science, Lund University, Lund, Sweden
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  • Arnab Bhattacherjee,

    1. Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden
    Current affiliation:
    1. Arnab Bhattacherjee's current address is Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
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  • Wouter Boomsma,

    1. Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden
    Current affiliation:
    1. Wouter Boomsma's current address is Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark
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  • Stefan Wallin,

    1. Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden
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  • Jens O. Lagerstedt,

    Corresponding author
    1. Department of Experimental Medical Science, Lund University, Lund, Sweden
    • Correspondence to: Jens O. Lagerstedt, Department of Experimental Medical Science, Lund University, BMC Floor C12, SE-221 84 Lund, Sweden. E-mail: jens.lagerstedt@med.lu.se and Anders Irbäck, Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Sölvegatan 14A, SE-223 62 Lund, Sweden. E-mail: anders@thep.lu.se

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  • Anders Irbäck

    Corresponding author
    1. Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden
    • Correspondence to: Jens O. Lagerstedt, Department of Experimental Medical Science, Lund University, BMC Floor C12, SE-221 84 Lund, Sweden. E-mail: jens.lagerstedt@med.lu.se and Anders Irbäck, Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Sölvegatan 14A, SE-223 62 Lund, Sweden. E-mail: anders@thep.lu.se

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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.

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