Structural characterization of covalently stabilized human cystatin c oligomers

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Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10–12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease.


  • Magdalena Chrabaszczewska
  • Adam K. Sieradzan
  • Sylwia Rodziewicz-Motowidło
  • Anders Grubb
  • Christopher M. Dobson
  • Janet R. Kumita
  • Maciej Kozak
Enheter & grupper
Externa organisationer
  • Adam Mickiewicz University in Poznań
  • University of Warsaw
  • Medical University of Gdansk
  • Skåne University Hospital
  • University of Cambridge

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi


Antal sidor17
TidskriftInternational Journal of Molecular Sciences
Utgåva nummer16
StatusPublished - 2020
Peer review utfördJa