| 131. |
- Hammarström, Per
(författare)
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Protein folding, misfolding and disease
- 2009
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Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 583:16, s. 2579-2580
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Tidskriftsartikel (refereegranskat)
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| 132. |
- Hammarström, Per, 1972-, et al.
(författare)
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Protein substrate binding induces conformational changes in the chaperonin GroEL : A suggested mechanism for unfoldase activity
- 2000
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 275:30, s. 22832-22838
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Tidskriftsartikel (refereegranskat)abstract
- Chaperonins are molecules that assist proteins during folding and protect them from irreversible aggregation. We studied the chaperonin GroEL and its interaction with the enzyme human carbonic anhydrase II (HCA II), which induces unfolding of the enzyme. We focused on conformational changes that occur in GroEL during formation of the GroEL-HCA II complex. We measured the rate of GroEL cysteine reactivity toward iodo[2-(14)C]acetic acid and found that the cysteines become more accessible during binding of a cysteine free mutant of HCA II. Spin labeling of GroEL with N-(1-oxy1-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide revealed that this additional binding occurred because buried cysteine residues become accessible during HCA II binding. In addition, a GroEL variant labeled with 6-iodoacetamidofluorescein exhibited decreased fluorescence anisotropy upon HCA II binding, which resembles the effect of GroES/ATP binding. Furthermore, by producing cysteine-modified GroEL with the spin label N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide and the fluorescent label 5-((((2-iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid, we detected increases in spin-label mobility and fluorescence intensity in GroEL upon HCA II binding. Together, these results show that conformational changes occur in the chaperonin as a consequence of protein substrate binding. Together with previous results on the unfoldase activity of GroEL, we suggest that the chaperonin opens up as the substrate protein binds. This opening mechanism may induce stretching of the protein, which would account for reported unfoldase activity of GroEL and might explain how GroEL can actively chaperone proteins larger than HCA II.
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| 133. |
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| 134. |
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| 135. |
- Hammarström, Per, et al.
(författare)
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Sequence-dependent denaturation energetics : A major determinant in amyloid disease diversity
- 2002
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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. ; 99:SUPPL. 4, s. 16427-16432
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Several misfolding diseases commence when a secreted folded protein encounters a partially denaturing microenvironment, enabling its self assembly into amyloid. Although amyloidosis is modulated by numerous environmental and genetic factors, single point mutations within the amyloidogenic protein can dramatically influence disease phenotype. Mutations that destabilize the native state predispose an individual to disease, however, thermodynamic stability alone does not reliably predict disease severity. Here we show that the rate of transthyretin (TTR) tetramer dissociation required for amyloid formation is strongly influenced by mutation (V30M, L55P, T119M, V122I), with rapid rates exacerbating and slow rates reducing amyloidogenicity. Although these rates are difficult to predict a priori, they notably influence disease penetrance and age of onset. L55P TTR exhibits severe pathology because the tetramer both dissociates quickly and is highly destabilized. Even though V30M and L55P TTR are similarly destabilized, the V30M disease phenotype is milder because V30M dissociates more slowly, even slower than wild type (WT). Although WT and V122I TTR have nearly equivalent tetramer stabilities, V122I cardiomyopathy, unlike WT cardiomyopathy, has nearly complete penetrance-presumably because of its 2-fold increase in dissociation rate. We show that the T119M homotetramer exhibits kinetic stabilization and therefore dissociates exceedingly slowly, likely explaining how it functions to protect V30M/T119M compound heterozygotes from disease. An understanding of how mutations influence both the kinetics and thermodynamics of misfolding allows us to rationalize the phenotypic diversity of amyloid diseases, especially when considered in concert with other genetic and environmental data.
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| 136. |
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| 137. |
- Hammarström, Per
(författare)
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The bloody path of amyloids and prions
- 2007
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:6
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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| 138. |
- Hammarström, Per
(författare)
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The dynamic amyloid landscape
- 2010
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Ingår i: The FEBS Journal. - : Wiley-Blackwell. - 1742-464X .- 1742-4658. ; 277:Suppl. 1, s. 14-14
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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| 139. |
- Hammarström, Per
(författare)
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The Transthyretin Protein and Amyloidosis - an Extraordinary Chemical Biology Platform
- 2024
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Ingår i: Israel Journal of Chemistry. - : WILEY-V C H VERLAG GMBH. - 0021-2148.
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Forskningsöversikt (refereegranskat)abstract
- The amyloidoses are diseases caused by accumulation of amyloid fibrils from over 40 different human misfolded proteins in various organs of the body depending on precursor protein. Amyloidogenesis is a self-perpetuating reaction with deleterious consequences causing degeneration in cells and organs where depositions occur. Transthyretin, TTR, is an amyloidogenic protein causing sporadic disease from the wild-type protein during aging and from numerous different autosomal dominant familial mutations at earlier ages depending on the sequence of the hereditary variant. Until recently the disease process was poorly understood, and therapies were scarce. Over the past decades, spurred by clinical data, using chemical biology research, the mechanisms of TTR production and misfolding have been elucidated affording almost complete coverage of the TTR amyloidogenesis pathway to be targeted. This translational science success has provided a plethora of therapeutic options for the TTR amyloidoses providing an inspiring example for success in previously intractable diseases. image
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| 140. |
- Hammarström, Per, et al.
(författare)
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Viruses and amyloids-a vicious liaison
- 2023
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Ingår i: Prion. - : TAYLOR & FRANCIS INC. - 1933-6896 .- 1933-690X. ; 17:1, s. 82-104
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Forskningsöversikt (refereegranskat)abstract
- The crosstalk between viral infections, amyloid formation and neurodegeneration has been discussed with varying intensity since the last century. Several viral proteins are known to be amyloidogenic. Post-acute sequalae (PAS) of viral infections is known for several viruses. SARS-CoV-2 and COVID-19 implicate connections between amyloid formation and severe outcomes in the acute infection, PAS and neurodegenerative diseases. Is the amyloid connection causation or just correlation? In this review we highlight several aspects where amyloids and viruses meet. The evolutionary driving forces that dictate protein amyloid formation propensity are different for viruses compared to prokaryotes and eukaryotes, while posttranslational endoproteolysis appears to be a common mechanism leading up to amyloid formation for both viral and human proteins. Not only do human and viral proteins form amyloid irrespective of each other but there are also several examples of co-operativity between amyloids, viruses and the inter-, and intra-host spread of the respective entity. Abnormal blood clotting in severe and long COVID and as a side effect in some vaccine recipients has been connected to amyloid formation of both the human fibrin and the viral Spike-protein. We conclude that there are many intersects between viruses and amyloids and, consequently, amyloid and virus research need to join forces here. We emphasize the need to accelerate development and implementation in clinical practice of antiviral drugs to preclude PAS and downstream neurological damage. There is also an ample need for retake on suitable antigen targets for the further development of next generation of vaccines against the current and coming pandemics.
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