Folding intermediates are involved in genetic diseases?

Bychkova, Valentina E.; Ptitsyn, Oleg B.

doi:10.1016/0014-5793(95)00004-s

Cited by 77 publications

(51 citation statements)

References 30 publications

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“…Elegant studies by Endo and Schatz revealed that the strong negative potential at the membrane surface attracts protons from the bulk solution resulting in a local decrease in pH, which consequently promotes the partial unfolding of proteins (46). Studies by Bychkova and Ptitsyn (47) and Wilkinson and Mayer (48) suggest that the membrane surface has a low dielectric constant. The acidic pH and the low dielectric constant at the membrane surface are shown to produce a denaturing microenvironment at the membrane surface.…”

Section: Discussion Possible Physiological Relevance Of the Partiallymentioning

confidence: 99%

Relevance of Partially Structured States in the Non-Classical Secretion of Acidic Fibroblast Growth Factor

et al. 2007

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Acidic fibroblast growth factor (aFGF) is a signal peptide-less protein that is secreted into the extracellular compartment as part of a multiprotein release complex, consisting of aFGF, S100A13 (a calcium binding protein), and a 40 kDa (p40) form of synaptotagmin (Syt1), a protein that participates in the docking of a variety of secretory vesicles. p40 Syt1, and specifically its C2A domain, is believed to play a major role in the non-classical secretion of the aFGF release complex mediated by the interaction of aFGF and p40 Syt1with the phospholipids of the cell membrane inner leaflet. In the present study, we investigate the structural characteristics of aFGF and the C2A domain of p40 Syt1 under acidic conditions, using a variety of biophysical techniques including multidimensional NMR spectroscopy. Urea-induced equilibrium unfolding (at pH 3.4) of both aFGF and the C2A domain are non-cooperative and proceed with the accumulation of stable intermediate states. 1-Anilino-8-napthalene sulfonate (ANS) binding and size-exclusion chromatography results suggest that both aFGF and the C2A domain exist as partially structured states under acidic conditions (pH 3.4). Limited trypsin digestion analysis and 1 H-15 N chemical shift perturbation data reveal that the flexibility of certain portions of the protein backbone is increased in the partially structured state(s) of aFGF. The residues that are perturbed in the partially structured state(s) in aFGF are mostly located at the N-and C-terminal ends of the protein. In marked contrast, most of the interactions stabilizing the native secondary structure are preserved in the partially structured state of the C2A domain. Isothermal titration calorimetry data indicate that the binding affinity between aFGF and the C2A domain is significantly enhanced at pH 3.4. In addition, both aFGF and the C2A domain exhibit much higher lipid binding affinity in

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Section: Discussion Possible Physiological Relevance Of the Partiallymentioning

confidence: 99%

Relevance of Partially Structured States in the Non-Classical Secretion of Acidic Fibroblast Growth Factor

et al. 2007

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“…Indeed, Yogalingam et al (16) recently demonstrated that mutations in NAGLU do indeed affect the stability and transiting of the enzyme through the secretory pathway. It is a well described phenomenon that many point mutations in proteins cause changes in folding that abolish proper trafficking (19,20). Ironically, in many cases, these physiologically disastrous mutations do not destroy the catalytic activity and may only cause slight folding anomalies (21).…”

Section: Insights Into Mps Iiibmentioning

confidence: 99%

Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB

Ficko-Blean

Stubbs²,

Nemirovsky³

et al. 2008

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

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“…It has been suggested (Bychkova & Ptitsyn, 1995) that the appearance of some genetic diseases can be due to the existence of protein mutations, which results in the termination of protein folding at the molten globule stage. The most intriguing in this assumption is that such diseases can be treated by means of "treatment" of non-native proteins with the use of drugs (Bychkova & Ptitsyn, 1995).…”

Section: Ligand-induced Mg -+ N Transition and Genetic Diseasesmentioning

confidence: 99%

“…The most intriguing in this assumption is that such diseases can be treated by means of "treatment" of non-native proteins with the use of drugs (Bychkova & Ptitsyn, 1995).…”

Section: Ligand-induced Mg -+ N Transition and Genetic Diseasesmentioning

confidence: 99%

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Circularly permuted dihydrofolate reductase possesses all the properties of the molten globule state, but can resume functional tertiary structure by interaction with its ligands

et al. 1996

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It is obvious that functional activity of a protein molecule is closely related to its structure. On the other hand, the understanding of structure‐function relationship still remains one of the intriguing problems of molecular biology. There is widespread belief that mutagenesis presents a real way to solve this problem. Following this assumption, we have investigated the effect of circular permutation in dihydrofolate reductase from E. coli on protein structure and functioning. It has been shown that in the absence of ligands two circularly permuted variants of dihydrofolate reductase possess all the properties of the molten globule state. However, after addition of ligands they gain the native‐like structural properties and specific activity. This means that the in vitro folding of permuted dihydrofolate reductase is terminated at the stage of the molten globule formation. Interaction of permuted protein with ligands leads to the structural adjustment and formation of active protein molecules.

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Folding intermediates are involved in genetic diseases?

Cited by 77 publications

References 30 publications

Relevance of Partially Structured States in the Non-Classical Secretion of Acidic Fibroblast Growth Factor

Relevance of Partially Structured States in the Non-Classical Secretion of Acidic Fibroblast Growth Factor

Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB

Circularly permuted dihydrofolate reductase possesses all the properties of the molten globule state, but can resume functional tertiary structure by interaction with its ligands

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