title: Comparative modeling of hypothetical amyloid pores based on cylindrin.
abstract: Cylindrin is a six-stranded antiparallel beta barrel obtained from amyloidogenic strands of crystallin. It induces cell toxicity through an unknown mechanism. In this work, the potential use of the structure of cylindrin as a template for modeling amyloid pores-hypothetical transmembrane structures which appear during amyloid diseases-was studied. Using comparative modeling (performed by Modeller), we tested the stability of cylindrin-based pores made from several amyloid-forming and non-amyloid-forming strands deriving from mutated cylindrin and the prion sup35. We showed that cylindrin could be used as a template for modeling pores made from strands of amyloid proteins, but that the cylindrin structure does not result from the amyloidogenicity of these fragments, as fibril non-formers from the prion were also able to form a similar structure. Finally, we tested whether the cellular toxicity of cylindrin and related structures could be due to its incorporation into the cell membrane, leading to the creation of conducting ionic channels. The results of modeling indicate that cylindrin and tandem-repeat cylindrin, mutants of them, and cylindrin-like amyloid pores from prion sequences can only localize on the periphery of the membrane, and are not able to conduct any ions into the cell. These findings explain experimental results obtained for large unilamellar vesicles incubated with cylindrin, where conductance was not observed.
authors.affiliation: Department of Biomedical Engineering, Wroclaw University of Technology, ul. Wybrzeze Wyspianskiego 27, 50-370, Wroclaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zulpo
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kotulska
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D001798:Blood Proteins; C031022:cylindrin