Unraveling the mysteries of protein folding and misfolding

  title={Unraveling the mysteries of protein folding and misfolding},
  author={Heath Ecroyd and John A. Carver},
  journal={IUBMB Life},
This mini‐review focuses on the processes and consequences of protein folding and misfolding. The latter process often leads to protein aggregation and precipitation with the aggregates adopting either highly ordered (amyloid fibril) or disordered (amorphous) forms. In particular, the amyloid fibril is discussed because this form has gained considerable notoriety due to its close links to a variety of debilitating diseases including Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt‐Jakob… 
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Functional and dysfunctional folding, association and aggregation of caseins.
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    Advances in protein chemistry and structural biology
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IM-MS is well suited to the study of protein misfolding, and has already yielded significant structural information for selected amyloidogenic systems during the aggregation process, a summary of current research highlighting how this methodology has unequivocally and unprecedentedly provided structural and mechanistic detail pertaining to the oligomerization of a variety of disease related proteins.
Specific mutations alter fibrillation kinetics, fiber morphologies, and membrane interactions of pentapeptides derived from human calcitonin.
This work indicates that the structural and kinetic properties of peptide fibrils as well as lipid interactions of fibrillar species are interrelated and are significantly affected by specific residues within amyloid peptide sequences.
Amyloid fibril recognition with the conformational B10 antibody fragment depends on electrostatic interactions.
The molecular chaperone β-casein prevents amorphous and fibrillar aggregation of α-lactalbumin by stabilisation of dynamic disorder
This study demonstrates how IM-MS and CIU can investigate the unfolding of proteins as well as examine transient and dynamic protein–chaperone interactions, and thereby provides detailed insight into the mechanism of chaperone action and proteostasis mechanisms.


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EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers
Redirection of amyloid fibril formation through the action of a small molecule is demonstrated, resulting in off-pathway, highly stable oligomers, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
Protein misfolding, functional amyloid, and human disease.
The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Dissociation from the Oligomeric State Is the Rate-limiting Step in Fibril Formation by κ-Casein*
Fibril formation by RCMκ-CN occurs through a novel mechanism whereby the rate-limiting step is the dissociation of an amyloidogenic precursor from an oligomeric state rather than the formation of stable nuclei, as has been described for most other fibril-forming systems.
Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.
Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.
Recent biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibril form that is typically observed at autopsy may actually be neuroprotective.
The structural basis of protein folding and its links with human disease.
  • C. Dobson
  • Biology
    Philosophical transactions of the Royal Society of London. Series B, Biological sciences
  • 2001
Evidence is accumulating that the formation of the highly organized amyloid aggregates is a generic property of polypeptides, and not simply a feature of the few proteins associated with recognized pathological conditions.
Designing conditions for in vitro formation of amyloid protofilaments and fibrils.
The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable.
Amyloid fibril formation by an SH3 domain.
Results indicate that the A state of PI3-SH3 is partially folded and support the hypothesis that partially folded states formed in solution are precursors of amyloid deposition.
Experimental investigation of protein folding and misfolding.