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The A beta 40 and A beta 42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

Cukalevski, Risto LU ; Yang, Xiaoting LU ; Meisl, Georg; Weininger, Ulrich LU ; Bernfur, Katja LU ; Frohm, Birgitta LU ; Knowles, Tuomas P. J. and Linse, Sara LU (2015) In Chemical Science 6(7). p.4215-4233
Abstract
The assembly of proteins into amyloid fibrils, a phenomenon central to several currently incurable human diseases, is a process of high specificity that commonly tolerates only a low level of sequence mismatch in the component polypeptides. However, in many cases aggregation-prone polypeptides exist as mixtures with variations in sequence length or post-translational modifications; in particular amyloid beta (A beta) peptides of variable length coexist in the central nervous system and possess a propensity to aggregate in Alzheimer's disease and related dementias. Here we have probed the co-aggregation and cross-seeding behavior of the two principal forms of A beta, A beta 40 and A beta 42 that differ by two hydrophobic residues at the... (More)
The assembly of proteins into amyloid fibrils, a phenomenon central to several currently incurable human diseases, is a process of high specificity that commonly tolerates only a low level of sequence mismatch in the component polypeptides. However, in many cases aggregation-prone polypeptides exist as mixtures with variations in sequence length or post-translational modifications; in particular amyloid beta (A beta) peptides of variable length coexist in the central nervous system and possess a propensity to aggregate in Alzheimer's disease and related dementias. Here we have probed the co-aggregation and cross-seeding behavior of the two principal forms of A beta, A beta 40 and A beta 42 that differ by two hydrophobic residues at the C-terminus. We find, using isotope-labeling, mass spectrometry and electron microscopy that they separate preferentially into homomolecular pure A beta 42 and A beta 40 structures during fibril formation from mixed solutions of both peptides. Although mixed fibrils are not formed, the kinetics of amyloid formation of one peptide is affected by the presence of the other form. In particular monomeric A beta 42 accelerates strongly the aggregation of A beta 40 in a concentration-dependent manner. Whereas the aggregation of each peptide is catalyzed by low concentrations of preformed fibrils of the same peptide, we observe a comparably insignificant effect when A beta 42 fibrils are added to A beta 40 monomer or vice versa. Therefore we conclude that fibril-catalysed nucleus formation and elongation are highly sequence specific events but A beta 40 and A beta 42 interact during primary nucleation. These results provide a molecular level description of homomolecular and heteromolecular aggregation steps in mixtures of polypeptide sequence variants. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemical Science
volume
6
issue
7
pages
4215 - 4233
publisher
Royal Society of Chemistry
external identifiers
  • wos:000356176200069
  • scopus:84935914041
ISSN
2041-6539
DOI
10.1039/c4sc02517b
language
English
LU publication?
yes
id
73d9a560-899f-43dd-8a3e-c765adeb10f3 (old id 7601908)
date added to LUP
2015-07-24 10:02:55
date last changed
2017-11-12 03:01:46
@article{73d9a560-899f-43dd-8a3e-c765adeb10f3,
  abstract     = {The assembly of proteins into amyloid fibrils, a phenomenon central to several currently incurable human diseases, is a process of high specificity that commonly tolerates only a low level of sequence mismatch in the component polypeptides. However, in many cases aggregation-prone polypeptides exist as mixtures with variations in sequence length or post-translational modifications; in particular amyloid beta (A beta) peptides of variable length coexist in the central nervous system and possess a propensity to aggregate in Alzheimer's disease and related dementias. Here we have probed the co-aggregation and cross-seeding behavior of the two principal forms of A beta, A beta 40 and A beta 42 that differ by two hydrophobic residues at the C-terminus. We find, using isotope-labeling, mass spectrometry and electron microscopy that they separate preferentially into homomolecular pure A beta 42 and A beta 40 structures during fibril formation from mixed solutions of both peptides. Although mixed fibrils are not formed, the kinetics of amyloid formation of one peptide is affected by the presence of the other form. In particular monomeric A beta 42 accelerates strongly the aggregation of A beta 40 in a concentration-dependent manner. Whereas the aggregation of each peptide is catalyzed by low concentrations of preformed fibrils of the same peptide, we observe a comparably insignificant effect when A beta 42 fibrils are added to A beta 40 monomer or vice versa. Therefore we conclude that fibril-catalysed nucleus formation and elongation are highly sequence specific events but A beta 40 and A beta 42 interact during primary nucleation. These results provide a molecular level description of homomolecular and heteromolecular aggregation steps in mixtures of polypeptide sequence variants.},
  author       = {Cukalevski, Risto and Yang, Xiaoting and Meisl, Georg and Weininger, Ulrich and Bernfur, Katja and Frohm, Birgitta and Knowles, Tuomas P. J. and Linse, Sara},
  issn         = {2041-6539},
  language     = {eng},
  number       = {7},
  pages        = {4215--4233},
  publisher    = {Royal Society of Chemistry},
  series       = {Chemical Science},
  title        = {The A beta 40 and A beta 42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation},
  url          = {http://dx.doi.org/10.1039/c4sc02517b},
  volume       = {6},
  year         = {2015},
}