Structural characterization of covalently stabilized human cystatin c oligomers
Chrabaszczewska, Magdalena ; Sieradzan, Adam K. ; Rodziewicz-Motowidło, Sylwia ; Grubb, Anders LU
; Dobson, Christopher M.
; Kumita, Janet R.
and Kozak, Maciej
(2020)
In International Journal of Molecular Sciences
21(16).
- Abstract
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... (More)
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.
(Less)
- author
- Chrabaszczewska, Magdalena
; Sieradzan, Adam K.
; Rodziewicz-Motowidło, Sylwia
; Grubb, Anders
LU
; Dobson, Christopher M.
; Kumita, Janet R.
and Kozak, Maciej
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cystatin C, Domain swapping, Oligomers, Protein misfolding
- in
- International Journal of Molecular Sciences
- volume
- 21
- issue
- 16
- article number
- 5860
- pages
- 17 pages
- publisher
- MDPI AG
- external identifiers
-
- pmid:32824145
- scopus:85089603448
- ISSN
- 1661-6596
- DOI
- 10.3390/ijms21165860
- language
- English
- LU publication?
- yes
- id
- fa057986-b016-4ddb-b7f9-3ed6238128fa
- date added to LUP
- 2020-08-27 13:25:20
- date last changed
- 2024-05-01 16:36:19
@article{fa057986-b016-4ddb-b7f9-3ed6238128fa,
abstract = {{<p>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.</p>}},
author = {{Chrabaszczewska, Magdalena and Sieradzan, Adam K. and Rodziewicz-Motowidło, Sylwia and Grubb, Anders and Dobson, Christopher M. and Kumita, Janet R. and Kozak, Maciej}},
issn = {{1661-6596}},
keywords = {{Cystatin C; Domain swapping; Oligomers; Protein misfolding}},
language = {{eng}},
number = {{16}},
publisher = {{MDPI AG}},
series = {{International Journal of Molecular Sciences}},
title = {{Structural characterization of covalently stabilized human cystatin c oligomers}},
url = {{http://dx.doi.org/10.3390/ijms21165860}},
doi = {{10.3390/ijms21165860}},
volume = {{21}},
year = {{2020}},
}