Energy landscapes of functional proteins are inherently risky

Gershenson, Anne; Gierasch, Lila M.; Pastore, Annalisa; Radford, Sheena E.

doi:10.1038/nchembio.1670

Cited by 99 publications

(91 citation statements)

References 108 publications

(121 reference statements)

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“…Furthermore, mutations in ubiquitin interfacing residues, or co-incubation with ubiquitin, slow the rate of Josephin domain aggregation (29). This has led to the intriguing hypothesis that protein function and aggregation are two competing pathways, whereby protein-protein binding can alleviate the risk of aggregation (29,41,42). Data reported here support this hypothesis and reveal that local molecular dynamics of helix-␣1 and helix-␣4 underlies this delicate balancing act.…”

Section: Discussionsupporting

confidence: 72%

Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

Lupton

Steer

Wintrode

et al. 2015

Journal of Biological Chemistry

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Background: Polyglutamine tract expansion within disease-associated proteins leads to protein aggregation and disease. Results: Molecular mobility of a single ␣-helix within ataxin-3 positively scales with polyglutamine tract length and drives misfolding and aggregation. Conclusion: Polyglutamine expansion allosterically enhances the molecular dynamics of folded regions to trigger amyloid-like fibril formation. Significance: This work resolves the mechanistic link between polyglutamine tract length and aggregation.

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Section: Discussionsupporting

confidence: 72%

Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

Lupton

Steer

Wintrode

et al. 2015

Journal of Biological Chemistry

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“…The cellular milieu is a precarious environment for the evolution of oligomeric proteins as the physical forces that drive beneficial protein association are the same as those that drive deleterious aggregation [26,27]. It is well established that changes in protein sequence through non-synonymous point mutations, insertions and deletions can shift the balance of oligomeric states [21,[28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Evolution of Protein Quaternary Structure in Response to Selective Pressure for Increased Thermostability

Fraser

Liu

Mabbitt

et al. 2016

Journal of Molecular Biology

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Oligomerization has been suggested to be an important mechanism for increasing or maintaining the thermostability of proteins. Although it is evident that protein-protein contacts can result in substantial stabilization in many extant proteins, evidence for evolutionary selection for oligomerization is largely indirect and little is understood of the early steps in the evolution of oligomers. A laboratory-directed evolution experiment that selected for increased thermostability in the αE7 carboxylesterase from the Australian sheep blowfly, Lucilia cuprina, resulted in a thermostable variant, LcαE7-4a, that displayed increased levels of dimeric and tetrameric quaternary structure. A trade-off between activity and thermostability was made during the evolution of thermostability, with the higher-order oligomeric species displaying the greatest thermostability and lowest catalytic activity. Analysis of monomeric and dimeric LcαE7-4a crystal structures revealed that only one of the oligomerization-inducing mutations was located at a potential protein-protein interface. This work demonstrates that by imposing a selective pressure demanding greater thermostability, mutations can lead to increased oligomerization and stabilization, providing support for the hypothesis that oligomerization is a viable evolutionary strategy for protein stabilization.

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“…[1][2][3][4][5][6][7][8] The initial pivotal step in amyloid assembly is considered to be the formation and accumulation of partially-unfolded intermediate state(s) of a protein, as a result of mutation in the amino acid sequence of the polypeptide chain or changes in solution conditions such as pH, ionic strength and temperature. 4,[9][10][11][12] The fact that nearly every protein can access the amyloid state, whether they are disease-associated or not, indicates that protein aggregation is a generic phenomenon and is likely to be independent of the native structure.…”

Section: Introductionmentioning

confidence: 99%

Self-Assembly of Ovalbumin Amyloid Pores: Effects on Membrane Permeabilization, Dipole Potential, and Bilayer Fluidity

Bhattacharya

Dogra

2015

Langmuir

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Amyloid assembly is inherently a stochastic and a hierarchical process comprising the genesis of heterogeneous, transiently populated prefibrillar aggregates that are characterized to be non-native oligomeric conformers. These oligomers could be either off-pathway or on-pathway species en route to amyloid fibrils that are associated with a variety of neurodegenerative disorders, namely, Alzheimer's disease, Parkinson's disease, and prion disease, as well as in localized and systemic amyloidoses (type II diabetes and dialysis related, respectively). Morphological characterizations of these prefibrillar aggregates indicated that apparently the doughnut or annular structure is commonly shared among various prefibrillar species irrespective of the diverse native structures and aggregation mechanisms. In this work, we have elucidated the self-assembly mechanism of amyloid pore formation from ovalbumin using a range of biophysical techniques that shed light on the time-dependent protein structural changes as aggregation progressed. Additionally, on the basis of several pieces of evidence suggesting amyloid pore-mediated cytotoxicity, we have investigated the annular amyloid-membrane interaction using a comprehensive biophysical approach. The influences of annular pores on the intramembrane dipole potential and bilayer fluidity, as a consequence of membrane permeabilization, were examined in a protein concentration- and time-dependent manner that provided important insights into the pore-membrane interactions. Instantaneous membrane permeabilization kinetics suggested that plausibly a detergent-like carpet mechanism during membrane disruption was effective. Moreover, it was inferred that a loss of membrane integrity resulted in the generation of both disordered lipid and disoriented water dipoles that reside in the immediate vicinity of the membrane bilayer. These key findings may have implications in amyloid-pore-induced deleterious effects during amyloid-membrane interactions.

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Energy landscapes of functional proteins are inherently risky

Cited by 99 publications

References 108 publications

Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

Evolution of Protein Quaternary Structure in Response to Selective Pressure for Increased Thermostability

Self-Assembly of Ovalbumin Amyloid Pores: Effects on Membrane Permeabilization, Dipole Potential, and Bilayer Fluidity

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