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Janowski, Robert; Kozak, Maciej; Jankowska, Elżbieta; Grzonka, Zbigniew; Grubb, Anders; Abrahamson, Magnus; Jaskólski, Mariusz

doi:10.1038/86188

Cited by 359 publications

(242 citation statements)

References 28 publications

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“…Tables 2 and 3 list the 10 most probable interprotein contacts found in aggregates. In both two-chain and four-chain systems, 9 of the 10 contacts are also native contacts, which indicates domain swapping, which has been observed as a mechanism of aggregation in numerous other systems (29)(30)(31)(32)(33).…”

Section: Resultsmentioning

confidence: 90%

Protein-folding landscapes in multichain systems

Cellmer

Bratko

Prausnitz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Computational studies of proteins have significantly improved our understanding of protein folding. These studies are normally carried out by using chains in isolation. However, in many systems of practical interest, proteins fold in the presence of other molecules. To obtain insight into folding in such situations, we compare the thermodynamics of folding for a Miyazawa-Jernigan model 64-mer in isolation to results obtained in the presence of additional chains. The melting temperature falls as the chain concentration increases. In multichain systems, free-energy landscapes for folding show an increased preference for misfolded states. Misfolding is accompanied by an increase in interprotein interactions; however, near the folding temperature, the transition from folded chains to misfolded and associated chains is entropically driven. A majority of the most probable interprotein contacts are also native contacts, suggesting that native topology plays a role in early stages of aggregation.computer simulation ͉ protein aggregation ͉ lattice model L attice-model proteins have played a key role in developing our understanding of protein folding. These model proteins contain enough detail to capture the essential physics of the folding process, yet are amenable to rigorous calculation of free-energy landscapes used to describe the folding pathway. Such calculations have provided a conceptual solution to the Levinthal Paradox, which ponders the ability of a protein to navigate a vast amount of conformational space to reach its native state on time scales of seconds or less (1-3). The funnellike nature of the free-energy landscapes, first calculated from lattice models, shows that proteins only need to sample a small fraction of conformations to reach the native state. The energetic bias toward the native state exists because native interactions are, on average, more stable than nonnative ones. Similar features are observed in folding landscapes generated from experiments, validating results from model calculations (1).Most computational studies of protein folding have examined a single chain in isolation (4-7). However, in many systems of practical interest, including in vivo folding, proteins fold in crowded environments. In such situations, interactions with other biological molecules compete with the intraprotein interactions that bias a protein's conformation toward its native state. Some biological molecules, such as molecular chaperones, promote folding (8). However, intermolecular interactions can also induce misfolding and aggregation (9, 10), resulting in loss of protein function (11). Further, protein aggregates can be toxic. Protein association has been linked to Ͼ20 human diseases, including Alzheimer's, Parkinson's, and Huntington's diseases (12, 13).We report simulations for systems containing one-, two-, or four-lattice model 64-mers. This chain length is greater than that in most model studies of multichain systems and correspondingly provides a more realistic surface area͞volume ratio than that for sm...

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Section: Resultsmentioning

confidence: 90%

Protein-folding landscapes in multichain systems

Cellmer

Bratko

Prausnitz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The stefin B dimers could be domain-swapped, similarly to stefin A dimers (22,23) and cystatin C dimers (39).…”

Section: Discussionmentioning

confidence: 99%

Interaction between Oligomers of Stefin B and Amyloid-β in Vitro and in Cells

Škerget

Taler‐Verčič

Bavdek

et al. 2010

Journal of Biological Chemistry

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To contribute to the question of the putative role of cystatins in Alzheimer disease and in neuroprotection in general, we studied the interaction between human stefin B (cystatin B) and amyloid-␤-(1-40) peptide (A␤). Using surface plasmon resonance and electrospray mass spectrometry we were able to show a direct interaction between the two proteins. As an interesting new fact, we show that stefin B binding to A␤ is oligomer specific. The dimers and tetramers of stefin B, which bind A␤, are domain-swapped as judged from structural studies. Consistent with the binding results, the same oligomers of stefin B inhibit A␤ fibril formation. When expressed in cultured cells, stefin B co-localizes with A␤ intracellular inclusions. It also co-immunoprecipitates with the APP fragment containing the A␤ epitope. Thus, stefin B is another APP/A␤-binding protein in vitro and likely in cells.Neurodegenerative diseases present a huge burden in the developed world's aging population. They are all in one way or another connected to aberrant protein folding and aggregation of the proteins involved (1). Various protein conformational disorders of the central and peripheral nervous system are known, which often appear sporadically but also run in families. These are among others: Parkinson and Alzheimer diseases, dementia with Lewy bodies, vascular and fronto-temporal dementia, and amyotrophic lateral sclerosis.The A␤ peptide implicated in Alzheimer disease pathology is a cleavage product of the membrane A␤ precursor protein (APP).3 It is the main constituent of extracellular amyloid plaques, however, together with its oligomers, it also resides intracellularly (2). It has been shown that A␤ oligomers prepared in vitro and those extracted from living cells exert cytotoxicity and cause symptoms of reversible memory loss in animal models (3). Amyloid protein oligomers have special structural properties, which are reflected in a common antioligomer antibody (4). This antibody not only binds the oligomers against which it was raised but also binds chaperones and some other proteins involved in disaggregating protein aggregates in cells (5). A␤-binding proteins, the so called "amateur chaperones," were suggested to have a potential in Alzheimer disease therapy (6, 7).It has been shown before that human cystatin C is an A␤-binding protein (8). Cystatins are single chain proteins that inhibit cysteine cathepsins (9). Human stefin B (also known as cystatin B) is a member of subfamily A of cystatins, classified as family I25 in the MEROPS scheme (10). Stefin B, a protein of 98 amino acid residues and 1 Cys, is predominantly intracellular, whereas cystatin C, a protein of 120 residues and 2 disulfide bonds, is a secretory protein. Three-dimensional structures of stefins and cystatin C have been determined, among others, the solution structure of stefin A (11) and cystatin C (12, 13).Human cystatin C has been found as a constituent of senile plaques of Alzheimer disease patients (14) and stefins A and B have also been reported to localize to a...

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confidence: 99%

“…The amyloid-forming protein cystatin C, which is the cause of a cerebral amyloidosis, is a key example. Certain mutants form amyloid fibrils and also undergo domain swapping, and inhibition of domain swapping also affects fibril formation (13)(14)(15)(16)(17). Domain swapping has also been proposed as an oligomeriza-tion mechanism for transthyretin (18), ␤2m (19 -21), and the prion protein (22,23), although arguably with less direct evidence to support these cases.…”

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confidence: 99%

Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions

Hoop

Kodali

et al. 2011

Journal of Biological Chemistry

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The formation of amyloid-like fibrils is characteristic of various diseases, but the underlying mechanism and the factors that determine whether, when, and how proteins form amyloid, remain uncertain. Certain mechanisms have been proposed based on the three-dimensional or runaway domain swapping, inspired by the fact that some proteins show an apparent correlation between the ability to form domain-swapped dimers and a tendency to form fibrillar aggregates. Intramolecular ␤-sheet contacts present in the monomeric state could constitute intermolecular ␤-sheets in the dimeric and fibrillar states. One example is an amyloid-forming mutant of the immunoglobulin binding domain B1 of streptococcal protein G, which in its native conformation consists of a four-stranded ␤-sheet and one ␣-helix. Under native conditions this mutant adopts a domainswapped dimer, and it also forms amyloid-like fibrils, seemingly in correlation to its domain-swapping ability. We employ magic angle spinning solid-state NMR and other methods to examine key structural features of these fibrils. Our results reveal a highly rigid fibril structure that lacks mobile domains and indicate a parallel in-register ␤-sheet structure and a general loss of native conformation within the mature fibrils. This observation contrasts with predictions that native structure, and in particular intermolecular ␤-strand interactions seen in the dimeric state, may be preserved in "domain-swapping" fibrils. We discuss these observations in light of recent work on related amyloidforming proteins that have been argued to follow similar mechanisms and how this may have implications for the role of domain-swapping propensities for amyloid formation.Amyloid fibril formation is characteristic of a variety of human disorders, including Huntington and Alzheimer diseases (1, 2). In amyloid-related diseases, one or more proteins are found in fibrillar aggregates, in a non-native, highly ␤-sheetrich conformation. Depending on the disease context, the propensity for amyloid formation may be traced to mutations and cleavage events, combined with poorly understood external triggers. Many proteins can also be made to form amyloid fibrils in vitro. Intriguingly, there are many accounts of proteins that form amyloid-like fibrils that are not associated with pathologies (2). Whether disease-related or not, amyloid fibrils share key biochemical and biophysical characteristics, suggesting common structural features. Understanding the fibril formation pathway is of interest not only as there may be a correlation between disease onset and protein aggregation, but also because transient oligomeric precursors may act as toxic species. However, a lack of high resolution structures of most fibrils and their precursors limits our knowledge of the mechanism of formation.One seemingly common structural motif for amyloid fibrils is an in-register parallel (IP) 3 assembly into pleated ␤-sheets, stabilized by backbone-to-backbone hydrogen bonding, combined with favorable side-chain interactions (e....

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Cited by 359 publications

References 28 publications

Protein-folding landscapes in multichain systems

Protein-folding landscapes in multichain systems

Interaction between Oligomers of Stefin B and Amyloid-β in Vitro and in Cells

Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions

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