| 1. |
- Johansson, Jan, et al.
(författare)
-
A novel anti-amyloid chaperone
- 2010
-
Ingår i: Amyloid. - 1350-6129 .- 1744-2818. ; 17, s. 103-104
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
|
|
| 2. |
|
|
| 3. |
- Nerelius, Charlotte, et al.
(författare)
-
Conformational preferences of non-polar amino acid residues: An additional factor in amyloid formation
- 2010
-
Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 402, s. 515-518
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid consists of beta-sheet polymers and is associated with disease and with functional assemblies Amyloid-forming proteins differ widely in native structures and sequences. We describe here how conformational preferences of non-polar amino acid residues can affect amyloid formation The most nonpolar residues promote either beta-strands (Val, Ile, Phe, and Cys. VIFC) or alpha-helices (Leu, Ala, and Met, LAM), while the most polar residues promote only alpha-helices. For 12 proteins associated with disease, the localizations of the amyloid core regions are known Eleven of these contain segments that are biased for VIFC, but essentially lack segments that are biased for LAM For the amyloid beta-peptide associated with Alzheimer's disease and an amyloidogenic fragment of the prion protein, observed effects of mutations support that VIFC bias favors formation of beta-sheet aggregates and arnyloid, while LAM bias prevents it VIFC and LAM profiles combine information on secondary structure propensities and polarity, and add a simple criterion to the prediction of amyloidogenic regions (C) 2010 Elsevier Inc All rights reserved
|
|
| 4. |
|
|
| 5. |
- Wik, Lotta, et al.
(författare)
-
Separate mechanisms act concurrently to shed and release the prion protein from the cell
- 2012
-
Ingår i: Prion. - : Informa UK Limited. - 1933-6896 .- 1933-690X. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- The cellular prion protein (PrPC) is attached to the cell membrane via its glycosylphosphatidylinositol (GPI)-anchor and is constitutively shed into the extracellular space. Here, three different mechanisms are presented that concurrently shed PrPC from the cell. The fast alpha-cleavage released a N-terminal fragment (N1) into the medium and the extreme C-terminal cleavage shed soluble full-length (FL-S) PrP and C-terminally cleaved (C1-S) fragments outside the cell. Also, a slow exosomal release of full-length (FL) and C1-fragment (C1) was demonstrated. The three separate mechanisms acting simultaneously, but with different kinetics, have to be taken into consideration when elucidating functional roles of PrPC and also when processing of PrPC is considered as a target for intervention in prion diseases. Further, in this study it was shown that metalloprotease inhibitors affected the extreme C-terminal cleavage and shedding of PrPC. The metalloprotease inhibitors did not influence the alpha-cleavage or the exosomal release. Taken together, these results are important for understanding the different mechanisms acting in parallel in the shedding and cleavage of PrPC.
|
|
| 6. |
- Willander, Hanna
(författare)
-
BRICHOS - a Novel Anti-Amyloid Chaperone : studies on pro-surfactant protein C
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung surfactant protein C (SP-C) is a 35-residue, transmembrane (TM) peptide that is extremely hydrophobic and lacks known homologous proteins. Due to a high content in Val residues in the α-helical TM part, SP-C can spontaneously convert into β-sheet aggregates. We show here that SP-C forms amyloid in interstitial lung disease (ILD) caused by mutations in the C-terminal part of proSP-C (CTC). CTC has been predicted to contain a ∼100-residue BRICHOS domain, found in 12 protein families with a wide range of functions and disease associations, such as respiratory distress syndrome, dementia and cancer. We hypothesised that the BRICHOS domain can act as a chaperone, preventing proprotein from misfolding during biosynthesis. Recombinant CTC can bind to lipid associated non-helical SP-C and this interaction results in an increased α-helical content in the mature SP-C peptide. Wildtype CTC can also stabilize proSP-C(1-58), which lacks the BRICHOS domain, and a proSP-C mutant in HEK293 cells. CTC binds selectively peptides derived from the TM part of SP-C and to residues that promote membrane insertion. CTC can also bind to other hydrophobic peptides, in particular the amyloid β-peptide (Aβ) associated with Alzheimer disease. CTC and Bri2 BRICHOS can prevent fibril formation of Aβ40 and Aβ42 far below stoichiometric amounts, indicating that BRICHOS may be useful in future therapy. The crystal structure of the BRICHOS domain from CTC shows a novel fold with a central β-sheet flanked by α-helices on either side. Many of the hydrophobic residues in the β-sheet are conserved and many of the point mutations associated with ILD coincide with these residues, suggesting that they are involved in the function of the BRICHOS domain possibly by binding substrate peptides. Taken together, results in this thesis, suggest that BRICHOS is a novel anti-amyloid chaperone domain and mutations that lead to BRICHOS dysfunction cause ILD and amyloid disease.
|
|
| 7. |
- Willander, Hanna, et al.
(författare)
-
BRICHOS domain associated with lung fibrosis, dementia and cancer - a chaperone that prevents amyloid fibril formation?
- 2011
-
Ingår i: FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 278, s. 3893-3904
-
Forskningsöversikt (refereegranskat)abstract
- The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD). Today BRICHOS has been found in 12 protein families. Mutations in the Bri2 and proSP-C genes result in familial dementia and ILD, respectively, and both these conditions are associated with amyloid formation. Amyloid is of great medical relevance as it is found in several major incurable diseases, like Alzheimer's and Parkinson's disease and diabetes mellitus. Work on recombinant BRICHOS domains and transfected cells indicate that BRICHOS is a chaperone domain that, during biosynthesis, binds to precursor protein regions with high beta-sheet propensities, thereby preventing them from amyloid formation. Regions prone to form beta-sheets are present in all BRICHOS-containing precursor proteins and are probably eventually released by proteolytic cleavage, generating different peptides with largely unknown bioactivities. Recombinant BRICHOS domains from Bri2 and proSP-C have been found to efficiently prevent SP-C, the amyloid beta-peptide associated with Alzheimer's disease, and medin, found in aortic amyloid, from forming amyloid fibrils. The data collected so far on BRICHOS raise several interesting topics for further research: (a) amyloid formation is a potential threat for many more proteins than the ones recognized so far in amyloid diseases; (b) amyloid formation of widely different peptides involves intermediate(s) that are recognized by the BRICHOS domain, suggesting that they have distinct structural similarities; and (c) the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases.
|
|
| 8. |
- Willander, Hanna, et al.
(författare)
-
BRICHOS Domains Efficiently Delay Fibrillation of Amyloid beta-Peptide
- 2012
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:37, s. 31608-31617
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 9. |
- Willander, Hanna, et al.
(författare)
-
High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:7, s. 2325-2329
-
Tidskriftsartikel (refereegranskat)abstract
- BRICHOS domains are encoded in >30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 angstrom crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.
|
|
| 10. |
- Willander, Hanna, et al.
(författare)
-
The Brichos domain of prosurfactant protein C can hold and fold a transmembrane segment
- 2009
-
Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 18, s. 1175-1182
-
Tidskriftsartikel (refereegranskat)abstract
- Prosurfactant protein C (proSP-C) is a 197-residue integral membrane protein, in which the C-terminal domain (CTC, positions 59-197) is localized in the endoplasmic reticulum (ER) lumen and contains a Brichos domain (positions 94-197). Mature SP-C corresponds largely to the transmembrane (TM) region of proSP-C. CTC binds to SP-C, provided that it is in nonhelical conformation, and can prevent formation of intracellular amyloid-like inclusions of proSP-C that harbor mutations linked to interstitial lung disease (ILD). Herein it is shown that expression of proSP-C (1-58), that is, the N-terminal propeptide and the TM region, in HEK293 cells results in virtually no detectable protein, while coexpression of CTC in trans yields SDS-soluble monomeric proSP-C (1-58). Recombinant human (rh) CTC binds to cellulose-bound peptides derived from the nonpolar TM region, but not the polar cytosolic part, of proSP-C, and requires >= 5-residues for maximal binding. Binding of rhCTC to a nonhelical peptide derived from SP-C results in a-helix formation provided that it contains a long TM segment. Finally, rhCTC and rhCTC Brichos domain shows very similar substrate specificities, but rhCTC(L188Q), a mutation linked to ILD is unable to bind all peptides analyzed. These data indicate that the Brichos domain of proSP-C is a chaperone that induces alpha-helix formation of an aggregation-prone TM region.
|
|
