Interactions in the native state of monellin, which play a protective role against aggregation.
(2011) In Molecular BioSystems 7. p.521-532- Abstract
- A series of recent studies have provided initial evidence about the role of specific intra-molecular interactions in maintaining proteins in their soluble state and in protecting them from aggregation. Here we show that the amino acid sequence of the protein monellin contains two aggregation-prone regions that are prevented from initiating aggregation by multiple non-covalent interactions that favor their burial within the folded state of the protein. By investigating the behavior of single-chain monellin and a series of five of its mutational variants using a variety of biochemical, biophysical and computational techniques, we found that weakening of the non-covalent interaction that stabilizes the native state of the protein leads to an... (More)
- A series of recent studies have provided initial evidence about the role of specific intra-molecular interactions in maintaining proteins in their soluble state and in protecting them from aggregation. Here we show that the amino acid sequence of the protein monellin contains two aggregation-prone regions that are prevented from initiating aggregation by multiple non-covalent interactions that favor their burial within the folded state of the protein. By investigating the behavior of single-chain monellin and a series of five of its mutational variants using a variety of biochemical, biophysical and computational techniques, we found that weakening of the non-covalent interaction that stabilizes the native state of the protein leads to an enhanced aggregation propensity. The lag time for fibrillation was found to correlate with the apparent midpoint of thermal denaturation for the series of mutational variants, thus showing that a reduced thermal stability is associated with an increased aggregation tendency. We rationalize these findings by showing that the increase in the aggregation propensity upon mutation can be predicted in a quantitative manner through the increase in the exposure to solvent of the amyloidogenic regions of the sequence caused by the destabilization of the native state. Our findings, which are further discussed in terms of the structure of monellin and the perturbation by the amino acid substitutions of the contact surface between the two subdomains that compose the folded state of monellin, provide a detailed description of the specific intra-molecular interactions that prevent aggregation by stabilizing the native state of a protein. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1732005
- author
- Szczepankiewicz, Olga LU ; Cabaleiro-Lago, Celia LU ; Tartaglia, Gian Gaetano ; Vendruscolo, Michele ; Hunter, Thérèse ; Hunter, Gary J ; Nilsson, Hanna LU ; Thulin, Eva LU and Linse, Sara LU
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular BioSystems
- volume
- 7
- pages
- 521 - 532
- publisher
- Royal Society of Chemistry
- external identifiers
-
- wos:000286390600026
- pmid:21076757
- scopus:78751666963
- pmid:21076757
- ISSN
- 1742-2051
- DOI
- 10.1039/c0mb00155d
- language
- English
- LU publication?
- yes
- id
- a1645f5b-6178-4d3f-80f5-2ac4c9008d40 (old id 1732005)
- date added to LUP
- 2016-04-01 13:59:30
- date last changed
- 2023-10-15 11:25:23
@article{a1645f5b-6178-4d3f-80f5-2ac4c9008d40,
abstract = {{A series of recent studies have provided initial evidence about the role of specific intra-molecular interactions in maintaining proteins in their soluble state and in protecting them from aggregation. Here we show that the amino acid sequence of the protein monellin contains two aggregation-prone regions that are prevented from initiating aggregation by multiple non-covalent interactions that favor their burial within the folded state of the protein. By investigating the behavior of single-chain monellin and a series of five of its mutational variants using a variety of biochemical, biophysical and computational techniques, we found that weakening of the non-covalent interaction that stabilizes the native state of the protein leads to an enhanced aggregation propensity. The lag time for fibrillation was found to correlate with the apparent midpoint of thermal denaturation for the series of mutational variants, thus showing that a reduced thermal stability is associated with an increased aggregation tendency. We rationalize these findings by showing that the increase in the aggregation propensity upon mutation can be predicted in a quantitative manner through the increase in the exposure to solvent of the amyloidogenic regions of the sequence caused by the destabilization of the native state. Our findings, which are further discussed in terms of the structure of monellin and the perturbation by the amino acid substitutions of the contact surface between the two subdomains that compose the folded state of monellin, provide a detailed description of the specific intra-molecular interactions that prevent aggregation by stabilizing the native state of a protein.}},
author = {{Szczepankiewicz, Olga and Cabaleiro-Lago, Celia and Tartaglia, Gian Gaetano and Vendruscolo, Michele and Hunter, Thérèse and Hunter, Gary J and Nilsson, Hanna and Thulin, Eva and Linse, Sara}},
issn = {{1742-2051}},
language = {{eng}},
pages = {{521--532}},
publisher = {{Royal Society of Chemistry}},
series = {{Molecular BioSystems}},
title = {{Interactions in the native state of monellin, which play a protective role against aggregation.}},
url = {{http://dx.doi.org/10.1039/c0mb00155d}},
doi = {{10.1039/c0mb00155d}},
volume = {{7}},
year = {{2011}},
}