uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
BRICHOS Domains Efficiently Delay Fibrillation of Amyloid beta-Peptide
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, 751 23 Uppsala, .
Show others and affiliations
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 37, 31608-31617 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid diseases such as Alzheimer, Parkinson, and prion diseases are associated with a specific form of protein mis-folding and aggregation into oligomers and fibrils rich in beta-sheet structure. The BRICHOS domain consisting of similar to 100 residues is found in membrane proteins associated with degenerative and proliferative disease, including lung fibrosis (surfactant protein C precursor; pro-SP-C) and familial dementia (Bri2). We find that recombinant BRICHOS domains from Bri2 and pro-SP-C prevent fibril formation of amyloid beta-peptides (A beta(40) and A beta(42)) far below the stoichiometric ratio. Kinetic experiments show that a main effect of BRICHOS is to prolong the lag time in a concentration-dependent, quantitative, and reproducible manner. An ongoing aggregation process is retarded if BRICHOS is added at any time during the lag phase, but it is too late to interfere at the end of the process. Results from circular dichroism and NMR spectroscopy, as well as analytical size exclusion chromatography, imply that A beta is maintained as an unstructured monomer during the extended lag phase in the presence of BRICHOS. Electron microscopy shows that although the process is delayed, typical amyloid fibrils are eventually formed also when BRICHOS is present. Structural BRICHOS models display a conserved array of tyrosine rings on a five-stranded beta-sheet, with inter-hydroxyl distances suited for hydrogen-bonding peptides in an extended beta-conformation. Our data imply that the inhibitory mechanism is reliant on BRICHOS interfering with molecular events during the lag phase.

Place, publisher, year, edition, pages
2012. Vol. 287, no 37, 31608-31617 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-183756DOI: 10.1074/jbc.M112.393157ISI: 000308791300072OAI: oai:DiVA.org:uu-183756DiVA: diva2:564990
Available from: 2012-11-05 Created: 2012-11-01 Last updated: 2014-10-15Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Presto, JennyKnight, Stefan D.Johansson, Jan
In the same journal
Journal of Biological Chemistry
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 198 hits
ReferencesLink to record
Permanent link

Direct link