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Bri2 BRICHOS domain: Eukaryotic expression and importance of strictly conserved cysteine residues
Linköping University, Department of Physics, Chemistry and Biology. (Jan Johansson)
2017 (English)Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
Abstract [en]

Alzheimer’s disease (AD), the most common form of dementia is associated with fibril formation of amyloid-ß peptides (Aß). Aß, proteolytically derived from Aß precursor protein (AßPP), is the major component of amyloid plaques in AD brains. Familial British and Danish dementias (FBD and FDD) share pathological and clinical characteristics with AD, and the underlying mechanisms are associated with amyloid formation of mutant peptides released from the Bri2 protein.

Bri2 interacts with AßPP and its BRICHOS domain has been shown to delay Aß40 and Aß42 fibril formation and toxicity in vitro and in vivo. This makes Bri2 BRICHOS a promising anti-amyloid chaperone and a potential treatment strategy for AD. Furthermore, Bri2 BRICHOS possesses a general chaperone activity as it suppresses non-fibrillar aggregation of destabilized citrate synthase (CS). Recent findings show that Bri2 BRICHOS produced in E.coli can form different molecular weight assemblies, ranging from monomers to dimers and poly-disperse oligomers. The oligomers inhibit CS aggregation, whereas the monomers and dimers are more efficient against Aß42 fibrillation and neurotoxicity, respectively.

The work in this thesis shows that similar Bri2 BRICHOS quaternary structures are formed in eukaryotic cells as in E.coli. Larger BRICHOS oligomers were found in cell media, derived from proteolytically processed endogenous Bri2 in SH-SY5Y cells, as well as in human embryonic kidney (HEK293) cells transfected with a Bri2 BRICHOS construct. Recombinant human Bri2 BRICHOS mutants with one or none of the two strictly conserved cysteine residues were studied. All mutant monomers become proteolytically degraded during purification, but form stable oligomers. Single Cys to Ser mutants form stable disulfide-dependent dimers that differ in ability to prevent Aß42 fibrillation, the most stable mutant (C164S) being even more efficient than the wildtype Bri2 BRICHOS dimer. This result suggests that intra or intermolecular disulfide(s) and oligomerization affect Bri2 BRICHOS stability and activity towards Aß42 fibril formation.

Place, publisher, year, edition, pages
2017. , p. 41
Keywords [en]
Bri2 BRICHOS, Aß, Chaperone, Amyloid fibril formation, Alzheimer disease, Eukaryotic expression, Cysteine residues
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-138401ISRN: LITH-IFM-A-EX--17/3302--SEOAI: oai:DiVA.org:liu-138401DiVA, id: diva2:1109888
External cooperation
Karolinska institutet, Institutionen för neurobiologi, vårdvetenskap och samhälle
Subject / course
Chemistry
Supervisors
Examiners
Available from: 2017-06-16 Created: 2017-06-14 Last updated: 2017-06-16Bibliographically approved

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