Small heat shock proteins (sHsps) are a ubiquitous and ancient family of ATP-independent molecular chaperones. A key characteristic of sHsps is that they exist in ensembles of iso-energetic ...oligomeric species differing in size. This property arises from a unique mode of assembly involving several parts of the subunits in a flexible manner. Current evidence suggests that smaller oligomers are more active chaperones. Thus, a shift in the equilibrium of the sHsp ensemble allows regulating the chaperone activity. Different mechanisms have been identified that reversibly change the oligomer equilibrium. The promiscuous interaction with non-native proteins generates complexes that can form aggregate-like structures from which native proteins are restored by ATP-dependent chaperones such as Hsp70 family members. In recent years, this basic paradigm has been expanded, and new roles and new cofactors, as well as variations in structure and regulation of sHsps, have emerged.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Organisms must survive a variety of stressful conditions, including sudden temperature increases that damage important cellular structures and interfere with essential functions. In response to heat ...stress, cells activate an ancient signaling pathway leading to the transient expression of heat shock or heat stress proteins (Hsps). Hsps exhibit sophisticated protection mechanisms, and the most conserved Hsps are molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures. In this Review, we summarize the concepts of the protective Hsp network.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small heat shock proteins (sHsps) are virtually ubiquitous molecular chaperones that can prevent the irreversible aggregation of denaturing proteins. sHsps complex with a variety of non-native ...proteins in an ATP-independent manner and, in the context of the stress response, form a first line of defense against protein aggregation in order to maintain protein homeostasis. In vertebrates, they act to maintain the clarity of the eye lens, and in humans, sHsp mutations are linked to myopathies and neuropathies. Although found in all domains of life, sHsps are quite diverse and have evolved independently in metazoans, plants and fungi. sHsp monomers range in size from approximately 12 to 42kDa and are defined by a conserved β-sandwich α-crystallin domain, flanked by variable N- and C-terminal sequences. Most sHsps form large oligomeric ensembles with a broad distribution of different, sphere- or barrel-like oligomers, with the size and structure of the oligomers dictated by features of the N- and C-termini. The activity of sHsps is regulated by mechanisms that change the equilibrium distribution in tertiary features and/or quaternary structure of the sHsp ensembles. Cooperation and/or co-assembly between different sHsps in the same cellular compartment add an underexplored level of complexity to sHsp structure and function.
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•A signature of all sHsps is a core α-crystallin domain that has a β-sandwich structure.•Most sHsps form large oligomers built in different geometries from a dimeric substructure.•sHsps can bind and stabilize diverse non-native proteins to maintain protein homeostasis.•sHsps evolved independently in different eukaryotes, potentially reflecting diverse functions.•Oligomeric sHsps exist as dynamic ensembles that are likely critical to their chaperone function.
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Small heat shock proteins (sHsps) are molecular chaperones involved in maintaining protein homeostasis; they have also been implicated in protein folding diseases and in cancer. In this protein ...family, a conserved core domain, the so-called α-crystallin or Hsp20 domain, is flanked by highly variable, nonconserved sequences that are essential for chaperone function. Analysis of 8714 sHsps revealed a broad variation of primary sequences within the superfamily as well as phyla-dependent differences. Significant variations were found in the number of sHsps per genome, their amino acid composition, and the length distribution of the different sequence parts. Reconstruction of the evolutionary tree for the sHsp superfamily shows that the flanking regions fall into several subgroups, indicating that they were remodeled several times in parallel but independent of the evolution of the α-crystallin domain. The evolutionary history of sHsps is thus set apart from that of other protein families in that two exon boundary-independent strategies are combined: the evolution of the conserved α-crystallin domain and the independent evolution of the N- and C-terminal sequences. This scenario allows for increased variability in specific small parts of the protein and thus promotes functional and structural differentiation of sHsps, which is not reflected in the general evolutionary tree of species.--Kriehuber, T., Rattei, T., Weinmaier, T., Bepperling, A., Haslbeck, M., Buchner, J. Independent evolution of the core domain and its flanking sequences in small heat shock proteins.
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mRNA splicing is required in about 4% of protein coding genes in Saccharomyces cerevisiae. The gene structure of those genes is simple, generally comprising two exons and one intron. In order to ...characterize the impact of alternative splicing on the S. cerevisiae transcriptome, we perform a systematic analysis of mRNA sequencing data. We find evidence of a pervasive use of alternative splice sites and detect several novel introns both within and outside protein coding regions. We also find a predominance of alternative splicing on the 3' side of introns, a finding which is consistent with existing knowledge on conservation of exon-intron boundaries in S. cerevisiae. Some of the alternatively spliced transcripts allow for a translation into different protein products.
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Life is resilient because living systems are able to respond to elevated temperatures with an ancient gene expression program called the heat shock response (HSR). In yeast, the transcription of ...hundreds of genes is upregulated at stress temperatures. Besides stress protection conferred by chaperones, the function of the majority of the upregulated genes under stress has remained enigmatic. We show that those genes are required to directly counterbalance increased protein turnover at stress temperatures and to maintain the metabolism. This anaplerotic reaction together with molecular chaperones allows yeast to efficiently buffer proteotoxic stress. When the capacity of this system is exhausted at extreme temperatures, aggregation processes stop translation and growth pauses. The emerging concept is that the HSR is modular with distinct programs dependent on the severity of the stress.
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•The HSR is modular and tuned to the severity of stress•90% of the upregulation under stress is required to keep protein levels constant•Protein loss under stress is replenished by translation•Aggregation processes shape the sublethal heat stress response
Mühlhofer et al. show that under mild and severe heat stress, proteins lost due to increased aggregation and degradation are replenished by increased protein synthesis to ensure a constant pool of proteins, together with the molecular chaperones. The heat shock response is activated in modules by transcriptional regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small heat shock proteins (sHsps) are molecular chaperones that prevent the aggregation of nonnative proteins. The sHsps investigated to date mostly form large, oligomeric complexes. The typical ...bacterial scenario seemed to be a two-component sHsps system of two homologous sHsps, such as the Escherichia coli sHsps IbpA and IbpB. With a view to expand our knowledge on bacterial sHsps, we analyzed the sHsp system of the bacterium Deinococcus radiodurans , which is resistant against various stress conditions. D. radiodurans encodes two sHsps, termed Hsp17.7 and Hsp20.2. Surprisingly, Hsp17.7 forms only chaperone active dimers, although its crystal structure reveals the typical α-crystallin fold. In contrast, Hsp20.2 is predominantly a 36mer that dissociates into smaller oligomeric assemblies that bind substrate proteins stably. Whereas Hsp20.2 cooperates with the ATP-dependent bacterial chaperones in their refolding, Hsp17.7 keeps substrates in a refolding-competent state by transient interactions. In summary, we show that these two sHsps are strikingly different in their quaternary structures and chaperone properties, defining a second type of bacterial two-component sHsp system.
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Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as ...the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world's experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12-15, 2016).
Abstract
Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions ...between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis. Here, we show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures. Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids. ACMs are thus promising leads for potent anti-amyloid drugs in both T2D and AD while the supramolecular nanofiber co-assemblies should inform the design of novel functional (hetero-)amyloid-based nanomaterials for biomedical/biotechnological applications.
The molecular chaperone αB-crystallin, the major player in maintaining the transparency of the eye lens, prevents stress-damaged and aging lens proteins from aggregation. In nonlenticular cells, it ...is involved in various neurological diseases, diabetes, and cancer. Given its structural plasticity and dynamics, structure analysis of αB-crystallin presented hitherto a formidable challenge. Here we present a pseudoatomic model of a 24-meric αB-crystallin assembly obtained by a triple hybrid approach combining data from cryoelectron microscopy, NMR spectroscopy, and structural modeling. The model, confirmed by cross-linking and mass spectrometry, shows that the subunits interact within the oligomer in different, defined conformations. We further present the molecular architectures of additional well-defined αB-crystallin assemblies with larger or smaller numbers of subunits, provide the mechanism how "heterogeneity" is achieved by a small set of defined structural variations, and analyze the factors modulating the oligomer equilibrium of αB-crystallin and thus its chaperone activity.
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