| 1. |
- Chen, G., et al.
(författare)
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Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue
- 2022
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Ingår i: RSC Chemical Biology. - : Royal Society of Chemistry (RSC). - 2633-0679. ; 3:11, s. 1342-1358
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Tidskriftsartikel (refereegranskat)abstract
- Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but to what extent the respective mechanisms are overlapping is not fully understood. The BRICHOS domain constitutes a disease-associated chaperone family, with activities against amyloid neurotoxicity, fibril formation, and amorphous protein aggregation. Here, we show that the activities of BRICHOS against amyloid-induced neurotoxicity and fibril formation, respectively, are oppositely dependent on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families. The conserved Asp in its ionized state promotes structural flexibility and has a pKa value between pH 6.0 and 7.0, suggesting that chaperone effects can be differently affected by physiological pH variations.
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| 2. |
- Brelsford, Christa, et al.
(författare)
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Developing a sustainability science approach for water systems
- 2020
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Ingår i: Ecology and Society. - 1708-3087. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- We convened a workshop to enable scientists who study water systems from both social science and physical science perspectives to develop a shared language. This shared language is necessary to bridge a divide between these disciplines’ different conceptual frameworks. As a result of this workshop, we argue that we should view socio-hydrological systems as structurally co-constituted of social, engineered, and natural elements and study the “characteristic management challenges” that emerge from this structure and reoccur across time, space, and socioeconomic contexts. This approach is in contrast to theories that view these systems as separately conceptualized natural and social domains connected by bi-directional feedbacks, as is prevalent in much of the water systems research arising from the physical sciences. A focus on emergent characteristic management challenges encourages us to go beyond searching for evidence of feedbacks and instead ask questions such as: What types of innovations have successfully been used to address these challenges? What structural components of the system affect its resilience to hydrological events and through what mechanisms? Are there differences between successful and unsuccessful strategies to solve one of the characteristic management challenges? If so, how are these differences affected by institutional structure and ecological and economic contexts? To answer these questions, social processes must now take center stage in the study and practice of water management. We also argue that water systems are an important class of coupled systems with relevance for sustainability science because they are particularly amenable to the kinds of systematic comparisons that allow knowledge to accumulate. Indeed, the characteristic management challenges we identify are few in number and recur over most of human history and in most geographical locations. This recurrence should allow us to accumulate knowledge to answer the above questions by studying the long historical record of institutional innovations to manage water systems.
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| 4. |
- Hedhammar, My, Professor, 1975-, et al.
(författare)
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Structural properties of recombinant nonrepetitive and repetitive parts of major ampullate spidroin 1 from Euprosthenops australis : implications for fiber formation
- 2008
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Ingår i: Journal of Biotechnology. - : American Chemical Society (ACS). - 0168-1656 .- 1873-4863. ; 47:11, s. 3407-17
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Tidskriftsartikel (refereegranskat)abstract
- Spider dragline silk proteins, spidroins, have a tripartite composition; a nonrepetitive N-terminal domain, a central repetitive region built up from many iterated poly-Ala and Gly rich blocks, and a C-terminal nonrepetitive domain. It is generally believed that the repetitive region forms intermolecular contacts in the silk fibers, while precise functions of the terminal domains have not been established. Herein, thermal, pH, and salt effects on the structure and aggregation and/or polymerization of recombinant N- and C-terminal domains, a repetitive segment containing four poly-Ala and Gly rich coblocks, and combinations thereof were studied. The N- and C-terminal domains have mainly alpha-helical structure, and interestingly, both form homodimers. Dimerization of the end domains allows spidroin multimerization independent of the repetitive part. Reduction of an intersubunit disulfide in the C-terminal domain lowers the thermal stability but does not affect dimerization. The repetitive region shows helical secondary structure but appears to lack stable folded structure. A protein composed of this repetitive region linked to the C-terminal domain has a mainly alpha-helical folded structure but shows an abrupt transition to beta-sheet structures upon heating. At room temperature, this protein self-assembles into macroscopic fibers within minutes. The secondary structures of none of the domains are altered by pH or salt. However, high concentrations of phosphate affect the tertiary structure and accelerate the aggregation propensity of the repetitive region. Implications of these results for dragline spidroin behavior in solution and silk fiber formation are discussed.
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| 6. |
- Kaldmäe, Margit, et al.
(författare)
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A “spindle and thread” mechanism unblocks p53 translation by modulating N-terminal disorder
- 2022
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Ingår i: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 30:5, s. 733-742, e1-e7
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Tidskriftsartikel (refereegranskat)abstract
- Disordered proteins pose a major challenge to structural biology. A prominent example is the tumor suppressor p53, whose low expression levels and poor conformational stability hamper the development of cancer therapeutics. All these characteristics make it a prime example of “life on the edge of solubility.” Here, we investigate whether these features can be modulated by fusing the protein to a highly soluble spider silk domain (NT∗). The chimeric protein displays highly efficient translation and is fully active in human cancer cells. Biophysical characterization reveals a compact conformation, with the disordered transactivation domain of p53 wrapped around the NT∗ domain. We conclude that interactions with NT∗ help to unblock translation of the proline-rich disordered region of p53. Expression of partially disordered cancer targets is similarly enhanced by NT∗. In summary, we demonstrate that inducing co-translational folding via a molecular “spindle and thread” mechanism unblocks protein translation in vitro.
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