Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution.
Dhulesia, Anne ; Cremades, Nunilo ; Kumita, Janet R ; Hsu, Shang-Te Danny ; Mossuto, Maria F ; Dumoulin, Mireille ; Nietlispach, Daniel ; Akke, Mikael LU
; Salvatella, Xavier
and Dobson, Christopher M
(2010)
In Journal of the American Chemical Society
132(44).
p.15580-15588
- Abstract
- The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal... (More)
- The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1711001
- author
- Dhulesia, Anne
; Cremades, Nunilo
; Kumita, Janet R
; Hsu, Shang-Te Danny
; Mossuto, Maria F
; Dumoulin, Mireille
; Nietlispach, Daniel
; Akke, Mikael
LU
; Salvatella, Xavier
and Dobson, Christopher M
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of the American Chemical Society
- volume
- 132
- issue
- 44
- pages
- 15580 - 15588
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000283955600039
- pmid:20958028
- scopus:78649728415
- pmid:20958028
- ISSN
- 1520-5126
- DOI
- 10.1021/ja103524m
- language
- English
- LU publication?
- yes
- id
- e11e42a8-62cf-4af4-a8e2-dbdd58c18d16 (old id 1711001)
- date added to LUP
- 2016-04-01 14:31:03
- date last changed
- 2022-04-22 03:41:01
@article{e11e42a8-62cf-4af4-a8e2-dbdd58c18d16,
abstract = {{The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein.}},
author = {{Dhulesia, Anne and Cremades, Nunilo and Kumita, Janet R and Hsu, Shang-Te Danny and Mossuto, Maria F and Dumoulin, Mireille and Nietlispach, Daniel and Akke, Mikael and Salvatella, Xavier and Dobson, Christopher M}},
issn = {{1520-5126}},
language = {{eng}},
number = {{44}},
pages = {{15580--15588}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution.}},
url = {{http://dx.doi.org/10.1021/ja103524m}},
doi = {{10.1021/ja103524m}},
volume = {{132}},
year = {{2010}},
}