Structural characterization of covalently stabilized human cystatin c oligomers

Chrabaszczewska, MagdalenaAdam Mickiewicz University in Poznań,University of Warsaw (author)

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.

Sieradzan, Adam K.Medical University of Gdansk (author)
Rodziewicz-Motowidło, SylwiaMedical University of Gdansk (author)
Grubb, AndersLund University,Lunds universitet,Cystatin C, njursjukdom, amyloidos och antibiotika,Forskargrupper vid Lunds universitet,Cystatin C, renal disease, amyloidosis and antibiotics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)kkem-agr (author)
Dobson, Christopher M.University of Cambridge (author)
Kumita, Janet R.University of Cambridge (author)
Kozak, MaciejAdam Mickiewicz University in Poznań (author)
Adam Mickiewicz University in PoznańUniversity of Warsaw (creator_code:org_t)

By the author/editor: Chrabaszczewska, ...; Sieradzan, Adam ...; Rodziewicz-Motow ...; Grubb, Anders; Dobson, Christop ...; Kumita, Janet R.; show more...; Kozak, Maciej; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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