Solubility of different folding conformers of bovine growth hormone

Brems, David N.

doi:10.1021/bi00412a048

Cited by 120 publications

(119 citation statements)

References 18 publications

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“…These problems were studied extensively (Ghélis and Yon, 1982;Mitraki et al, 1987;Brems, 1988;Lehrman et al, 1991;Cleland and Wang, 1990), with the general conclusions that folding intermediates with a partially exposed hydrophobic core are responsible for the aggregation and precipitation (Wetzel, 1992;Mitraki and King, 1989). The dimerization of cystatin C (leading to precipitation at higher concentrations) resembles other systems by exhibiting a characteristic trough (Ghélis and Yon, 1982) under conditions directly preceding unfolding.…”

Section: Discussionmentioning

confidence: 99%

Folding-related Dimerization of Human Cystatin C

Ekiel

Abrahamson

1996

Journal of Biological Chemistry

122

101

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With the aim to improve our understanding of the structural basis for protein self-association and aggregation, in particular in relationship to protein refolding and amyloid formation, folding-related processes for human cystatin C have been studied. Using NMR spectroscopy together with chromatographic and electrophoretic methods, a self-association process resulting in dimer formation for protein samples treated with denaturing agents as well as for samples subjected to low pH or high temperature conditions could be studied with amino acid resolution. In all three cases, the dimerization involves properly folded molecules and proceeds via the reactive site of the inhibitor, which leads to complete loss of its biological activity. This dimerization process has potential relevance for amyloid formation by the brain hemorrhage-causing Leu 68 -Gln variant of cystatin C. The results also indicate that cystatin C dimerization and inactivation may occur in acidified compartments in vivo, which could be relevant for the physiological regulation of cysteine proteinase activity.The self-association and aggregation of proteins constitutes one of the least understood problems in protein chemistry.

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Section: Discussionmentioning

confidence: 99%

Folding-related Dimerization of Human Cystatin C

Ekiel

Abrahamson

1996

Journal of Biological Chemistry

122

101

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“…The unfolded bGH partitions between the aggregated and the native states (19). Remarkably, addition of a specific peptide fragment (amino acids 96-133) of bGH can block aggregation.…”

Section: Partly Folded Intermediate States In the Folding And Aggregamentioning

confidence: 99%

Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions

2002

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Figure 1Funnels representing an idealized energy landscape for protein folding (a) or a rugged energy landscape with kinetic traps (b), from models of Dill and Chan (80). (a) The unfolded chain starts at the top of an energy landscape, and, as it forms intrachain contacts, lowering its free energy (and descending the funnel), the number of conformations it can sample is progressively reduced, thus eliminating the need for a global search. Ultimately, it reaches the unique native state at the energetic minimum. Note that the number of pathways typically available coming down from the unfolded state may not be unlimited, as depicted here, but may be multiple. (b) Descending a rugged landscape, the polypeptide can lodge in a kinetic trap or can alternatively descend through a narrow path to the native state. Molecular chaperones may act to "smooth" rugged landscapes, preventing polypeptide from descending into a kinetic trap, or rescuing it from one. Reproduced with permission from Nature Structural Biology (80). N, native state.

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“…The difference may be that barnase collapses rapidly into a folding intermediate (3) which is more soluble than the unfolded protein. Aggregation is observed also during refolding of larger proteins-e.g., bovine growth hormone (25), reduced lysozyme (26), and phosphoglycerate kinase (27). Since these proteins fold much more slowly than U1A there is ample of time for aggregation to occur, and the implications of the results for rapidly folding proteins are uncertain.…”

Section: Could Concealed Aggregation Be a General Problem In Folding mentioning

confidence: 99%

Transient aggregates in protein folding are easily mistaken for folding intermediates

Silow

Oliveberg

1997

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

169

164

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It has been questioned recently whether populated intermediates are important for the protein folding process or are artefacts trapped in nonproductive pathways. We report here that the rapidly formed intermediate of the spliceosomal protein U1A is an off-pathway artefact caused by transient aggregation of denatured protein under native conditions. Transient aggregates are easily mistaken for structured monomers and could be a general problem in timeresolved folding studies.

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Solubility of different folding conformers of bovine growth hormone

Cited by 120 publications

References 18 publications

Folding-related Dimerization of Human Cystatin C

Folding-related Dimerization of Human Cystatin C

Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions

Transient aggregates in protein folding are easily mistaken for folding intermediates

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