| 1. |
- Botelho, Hugo M., et al.
(författare)
-
S100A6 Amyloid Fibril formation is Calcium-modulated and enhances Superoxide Dismutase-1 (SOD1) aggregation
- 2012
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:50, s. 42233-42242
-
Tidskriftsartikel (refereegranskat)abstract
- S100A6 is a small EF-hand calcium- and zinc-binding protein involved in the regulation of cell proliferation and cytoskeletal dynamics. It is overexpressed in neurodegenerative disorders and a proposed marker for Amyotrophic Lateral Sclerosis (ALS). Following recent reports of amyloid formation by S100 proteins, we investigated the aggregation properties of S100A6. Computational analysis using aggregation predictors Waltz and Zyggregator revealed increased propensity within S100A6 helices HI and HIV. Subsequent analysis of Thioflavin-T binding kinetics under acidic conditions elicited a very fast process with no lag phase and extensive formation of aggregates and stacked fibrils as observed by electron microscopy. Ca2+ exerted an inhibitory effect on the aggregation kinetics, which could be reverted upon chelation. An FT-IR investigation of the early conformational changes occurring under these conditions showed that Ca2+ promotes anti-parallel beta-sheet conformations that repress fibrillation. At pH 7, Ca2+ rendered the fibril formation kinetics slower: time-resolved imaging showed that fibril formation is highly suppressed, with aggregates forming instead. In the absence of metals an extensive network of fibrils is formed. S100A6 oligomers, but not fibrils, were found to be cytotoxic, decreasing cell viability by up to 40%. This effect was not observed when the aggregates were formed in the presence of Ca2+. Interestingly, native S1006 seeds SOD1 aggregation, shortening its nucleation process. This suggests a cross-talk between these two proteins involved in ALS. Overall, these results put forward novel roles for S100 proteins, whose metalmodulated aggregation propensity may be a key aspect in their physiology and function.
|
|
| 2. |
- Carvalho, Sofia B., et al.
(författare)
-
Structural heterogeneity and bioimaging of S100 amyloid assemblies
- 2014
-
Ingår i: Bio-nanoimaging. - : Academic Press. - 9780123944313 ; , s. 197-212
-
Bokkapitel (refereegranskat)abstract
- S100 proteins are small EF-hand Ca2+-binding proteins involved in diverse cellular processes such as cell survival, proliferation and differentiation. Many S100 proteins also bind additional metal ions which modulate their folding and activity. The expression levels of many S100 proteins are significantly increased in cancer, neurodegenerative, inflammatory and autoimmune diseases. Recently, S100A8/A9 were identified as major amyloidogenic proteins in corpora amylacea inclusions of prostate cancer patients and found to undergo metal-mediated amyloid oligomerization and fibrillation in vitro. The amyloidogenic potential has also been found in other S100 family members, suggesting that amyloid-like assemblies may play an important role in S100 biologic activity in health and disease. In this chapter we address the structural diversity of S100 aggregates, as revealed by high-resolution bioimaging techniques. We start by overviewing the structural diversity of individual S100 proteins and their functional oligomers; this is followed by analysis of their amyloidogenic aggregation potential, general characterization of S100 amyloids, and the role of metal ions in aggregation pathways. The morphologic diversity of the aggregates formed by different types of S100 protein is illustrated by electron and atomic force microscopy data. The chapter ends by overviewing the amyloid formation by S100A8/A9 in the aging prostate, showing how microscopy techniques can be used to characterize in vitro and ex vivo amyloids.
|
|
| 3. |
- Fritz, Günter, et al.
(författare)
-
Natural and amyloid self-assembly of S100 proteins : structural basis of functional diversity
- 2010
-
Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 277:22, s. 4578-4590
-
Tidskriftsartikel (refereegranskat)abstract
- The S100 proteins are 10-12 kDa EF-hand proteins that act as central regulators in a multitude of cellular processes including cell survival, proliferation, differentiation and motility. Consequently, many S100 proteins are implicated and display marked changes in their expression levels in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases. The structure and function of S100 proteins are modulated by metal ions via Ca(2+) binding through EF-hand motifs and binding of Zn(2+) and Cu(2+) at additional sites, usually at the homodimer interfaces. Ca(2+) binding modulates S100 conformational opening and thus promotes and affects the interaction with p53, the receptor for advanced glycation endproducts and Toll-like receptor 4, among many others. Structural plasticity also occurs at the quaternary level, where several S100 proteins self-assemble into multiple oligomeric states, many being functionally relevant. Recently, we have found that the S100A8/A9 proteins are involved in amyloidogenic processes in corpora amylacea of prostate cancer patients, and undergo metal-mediated amyloid oligomerization and fibrillation in vitro. Here we review the unique chemical and structural properties of S100 proteins that underlie the conformational changes resulting in their oligomerization upon metal ion binding and ultimately in functional control. The possibility that S100 proteins have intrinsic amyloid-forming capacity is also addressed, as well as the hypothesis that amyloid self-assemblies may, under particular physiological conditions, affect the S100 functions within the cellular milieu.
|
|
| 4. |
- Lang, Daniel, et al.
(författare)
-
The Physcomitrella patens chromosome-scale assembly reveals moss genome structure and evolution
- 2018
-
Ingår i: The Plant Journal. - : Wiley. - 0960-7412 .- 1365-313X. ; 93:3, s. 515-533
-
Tidskriftsartikel (refereegranskat)abstract
- The draft genome of the moss model, Physcomitrella patens, comprised approximately 2000 unordered scaffolds. In order to enable analyses of genome structure and evolution we generated a chromosome-scale genome assembly using genetic linkage as well as (end) sequencing of long DNA fragments. We find that 57% of the genome comprises transposable elements (TEs), some of which may be actively transposing during the life cycle. Unlike in flowering plant genomes, gene-and TE-rich regions show an overall even distribution along the chromosomes. However, the chromosomes are mono-centric with peaks of a class of Copia elements potentially coinciding with centromeres. Gene body methylation is evident in 5.7% of the protein-coding genes, typically coinciding with low GC and low expression. Some giant virus insertions are transcriptionally active and might protect gametes from viral infection via siRNA mediated silencing. Structure-based detection methods show that the genome evolved via two rounds of whole genome duplications (WGDs), apparently common in mosses but not in liverworts and hornworts. Several hundred genes are present in colinear regions conserved since the last common ancestor of plants. These syntenic regions are enriched for functions related to plant-specific cell growth and tissue organization. The P. patens genome lacks the TE-rich pericentromeric and gene-rich distal regions typical for most flowering plant genomes. More non-seed plant genomes are needed to unravel how plant genomes evolve, and to understand whether the P. patens genome structure is typical for mosses or bryophytes.
|
|
| 5. |
- Schmidt, Matthias, et al.
(författare)
-
Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis
- 2019
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 angstrom cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.
|
|
| 6. |
- Türk, Karin, et al.
(författare)
-
NADH oxidation by the Na+-translocating NADH : quinone oxidoreductase from Vibrio cholerae
- 2004
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:20, s. 21349-21355
-
Tidskriftsartikel (refereegranskat)abstract
- The Na(+)-translocating NADH:quinone oxidoreductase from Vibrio cholerae is a six subunit enzyme containing four flavins and a single motif for the binding of a Fe-S cluster on its NqrF subunit. This study reports the production of a soluble variant of NqrF (NqrF') and its individual flavin and Fe-S-carrying domains using V. cholerae or Escherichia coli as expression hosts. NqrF' and the flavin domain each contain 1 mol of FAD/mol of enzyme and exhibit high NADH oxidation activity (20,000 micromol min(-1) mg(-1)). EPR, visible absorption, and circular dichroism spectroscopy indicate that the Fe-S cluster in NqrF' and its Fe-S domain is related to 2Fe ferredoxins of the vertebrate-type. The addition of NADH to NqrF' results in the formation of a neutral flavosemiquinone and a partial reduction of the Fe-S cluster. The NqrF subunit harbors the active site of NADH oxidation and acts as a converter between the hydride donor NADH and subsequent one-electron reaction steps in the Na(+)-translocating NADH:quinone oxidoreductase complex. The observed electron transfer NADH --> FAD --> [2Fe-2S] in NqrF requires positioning of the FAD and the Fe-S cluster in close proximity in accordance with a structural model of the subunit.
|
|
