Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis

Sorimachi, K. and Craik, D. J. (1994) Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis. European Journal of Biochemistry, 219 1-2: 237-251. doi:10.1111/j.1432-1033.1994.tb19935.x


Author Sorimachi, K.
Craik, D. J.
Title Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis
Journal name European Journal of Biochemistry   Check publisher's open access policy
ISSN 0014-2956
Publication date 1994-01-01
Sub-type Article (original research)
DOI 10.1111/j.1432-1033.1994.tb19935.x
Volume 219
Issue 1-2
Start page 237
End page 251
Total pages 15
Place of publication West Sussex, United Kingdom
Publisher Wiley-Blackwell
Language eng
Formatted abstract
Amyloid deposition is a biochemical and histopathologic hallmark of various clinical forms of amyloidoses including Alzheimer's disease and the Dutch-type hereditary cerebral haemorrhage with amyloidosis. The self- aggregating peptides responsible for these irreversible deposits have been sequenced but the mechanisms involved in the aggregation processes are not well understood. In order to gain an understanding of the possible structures prior to self-association, the extracellular fragment of the Alzheimer amyloid protein (βA4) responsible for the deposits (the 'native' fragment) and a mutant of this with a single residue substitution (which is responsible for deposits in the Dutch-type amyloidosis) were examined by 1H-NMR spectroscopy. Interproton distance constraints were derived from NMR experimental data and incorporated into tertiary structure calculations using a simulated annealing protocol. Solution conformations of the fragment peptides associated with the two forms of amyloidoses are presented and compared. Although in both peptides the existence of a mixture of conformations in equilibrium is likely, one such population of structures possesses a flexible N-terminus and a well defined C-terminal region. The latter region includes a helical segment and a terminal turn-like structure. These structural features may be important for the basis of amyloid formation. Comparison of the calculated structures of the two peptides revealed a conformationally different region arising from the conservative substitution of Gln22 for Glu22. This region may be responsible for altered binding in the mutant peptide, giving rise to the clinically different form of amyloidosis.
Keyword Protease Inhibitor Domain
Mhz Nmr-Spectra
Beta-Protein
Conformational-Analysis
Secondary-Structure
Precursor Protein
Fibril Formation
Linear Peptides
H-1-Nmr Spectra
Assignment
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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