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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)
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author
organization
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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
external identifiers
  • wos:000283955600039
  • pmid:20958028
  • scopus:78649728415
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
2010-11-05 11:09:50
date last changed
2018-05-29 12:11:41
@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},
  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},
  volume       = {132},
  year         = {2010},
}