Thermodynamics of Conformational Transitions in a Disordered Protein Backbone Model

Drake, Justin A.; Pettitt, B. Montgomery

doi:10.1016/j.bpj.2018.04.027

Cited by 15 publications

(23 citation statements)

References 79 publications

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“…IDP/IDPRs are characterized by low sequence complexity and biased amino acid composition (preference for highly charged and hydrophilic residues) [58]. The lack of hydrophobic/bulky residues results in a relatively flat energy surface and existence as a structural “ensemble” of interconverting conformational states [62]. Disordered regions leverage their high conformational freedom to maximize potential binding partners (Figure 1).…”

Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

Proteasome Activation to Combat Proteotoxicity

Jones

Tepe

2019

Molecules

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Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

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Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

Proteasome Activation to Combat Proteotoxicity

Jones

Tepe

2019

Molecules

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“…However, just because a protein segment can't be resolved crystallographically doesn't mean that it is unimportant for protein function. It has recently been recognised that intrinsically disordered regions of proteins can play an important part in the thermodynamics of protein conformational transitions [67,68]. Changes in protein backbone and side-chain conformational entropy are thought to make major contributions to protein folding and to the regulation of protein activity [69,70].…”

Section: Discussionmentioning

confidence: 99%

Polarity of the ATP binding site of the Na+,K+-ATPase, gastric H+,K+-ATPase and sarcoplasmic reticulum Ca2+-ATPase

Hossain¹,

Li²,

Zhang³

et al. 2020

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A fluorescence ratiometric method utilising the probe eosin Y is presented for estimating the ATP binding site polarity of P-type ATPases in different conformational states. The method has been calibrated by measurements in a series of alcohols and tested using complexation of eosin Y with methyl-β-cyclodextrin. The results obtained with the Na + ,K +-, H + ,K +-and sarcoplasmic reticulum Ca 2+-ATPases indicate that the ATP binding site, to which eosin is known to bind, is significantly more polar in the case of the Na + ,K +-and H + ,K +-ATPases compared to the Ca 2+-ATPase. This result was found to be consistent with docking calculations of eosin with the E2 conformational state of the Na + ,K +-ATPase and the Ca 2+-ATPase. Fluorescence experiments showed that eosin binds significantly more strongly to the E1 conformation of the Na + ,K +-ATPase than the E2 conformation, but in the case of the Ca 2+-ATPase both fluorescence experiments and docking calculations showed no significant difference in binding affinity between the two conformations. This result could be due to the fact that, in contrast to the Na + ,K +-and H + ,K +-ATPases, the E2-E1 transition of the Ca 2+-ATPase does not involve the movement of a lysine-rich N-terminal tail which may affect the overall enzyme conformation. Consistent with this hypothesis, the eosin affinity of the E1 conformation of the Na + ,K +-ATPase was significantly reduced after N-terminal truncation. It is suggested that changes in conformational entropy of the N-terminal tail of the Na + , K +-and the H + ,K +-ATPases during the E2-E1 transition could affect the thermodynamic stability of the E1 conformation and hence its ATP binding affinity.

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“…Apart from promoting the interaction with binding partners, it has recently become recognized that intrinsically disordered regions of proteins can themselves play an important role in the thermodynamics of protein conformational transitions (Wand 2013;Drake and Pettitt 2018). If a protein conformational change occurs which involves a transition of a protein segment, such as the N-terminus, from an ordered to a disordered state, the conformational entropy thus gained must cause a decrease in free energy and hence a stabilisation of the resultant protein conformation.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Analysis of the Lysine-Rich N-terminal Cytoplasmic Domains of the Gastric H+,K+-ATPase and the Na+,K+-ATPase

Diaz

Clarke

2018

J Membrane Biol

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The catalytic α-subunits of both the Na,K-ATPase and the gastric H,K-ATPase possess lysine-rich N-termini which project into the cytoplasm. Due to conflicting experimental results, it is currently unclear whether the N-termini play a role in ion pump function or regulation, and, if they do, by what mechanism. Comparison of the lysine frequencies of the N-termini of both proteins with those of all of their extramembrane domains showed that the N-terminal lysine frequencies are far higher than one would expect simply from exposure to the aqueous solvent. The lysine frequency was found to vary significantly between different vertebrate classes, but this is due predominantly to a change in N-terminal length. As evidenced by a comparison between fish and mammals, an evolutionary trend towards an increase of the length of the N-terminus of the H,K-ATPase on going from an ancestral fish to mammals could be identified. This evolutionary trend supports the hypothesis that the N-terminus is important in ion pump function or regulation. In placental mammals, one of the lysines is replaced by serine (Ser-27), which is a target for protein kinase C. In most other animal species, a lysine occupies this position and hence no protein kinase C target is present. Interaction with protein kinase C is thus not the primary role of the lysine-rich N-terminus. The disordered structure of the N-terminus may, via increased flexibility, facilitate interaction with another binding partner, e.g. the surrounding membrane, or help to stabilise particular enzyme conformations via the increased entropy it produces.

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Thermodynamics of Conformational Transitions in a Disordered Protein Backbone Model

Cited by 15 publications

References 79 publications

Proteasome Activation to Combat Proteotoxicity

Proteasome Activation to Combat Proteotoxicity

Polarity of the ATP binding site of the Na+,K+-ATPase, gastric H+,K+-ATPase and sarcoplasmic reticulum Ca2+-ATPase

Evolutionary Analysis of the Lysine-Rich N-terminal Cytoplasmic Domains of the Gastric H+,K+-ATPase and the Na+,K+-ATPase

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