scholarly journals Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins

2022 ◽  
Author(s):  
Xiangze Zeng ◽  
Kiersten M Ruff ◽  
Rohit V Pappu
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Free Energies ◽  
Stable States ◽  
State Behavior ◽  
Solvent Interactions ◽  
Intrinsically Disordered ◽  
Charged Residues ◽  
Oppositely Charged ◽  
Self Avoiding Walks

The most commonly occurring intrinsically disordered proteins (IDPs) are polyampholytes, which are defined by the duality of low net charge per residue and high fractions of charged residues. Recent experiments have uncovered surprises regarding sequence-ensemble relationships of model polyampholytic IDPs. These include differences in conformational preferences for sequences with lysine vs. arginine, and the suggestion that well-mixed sequences either form globules or conformations with ensemble averages that are reminiscent of ideal chains wherein intra-chain and chain-solvent interactions are counterbalanced. Here, we explain these observations by analyzing results from atomistic simulations. We find that polyampholytic IDPs generally sample two distinct stable states, namely globules and self-avoiding walks. Globules are favored by electrostatic attractions between oppositely charged residues, whereas self-avoiding walks are favored by favorable free energies of hydration of charged residues. We find sequence-specific temperatures of bistability at which globules and self-avoiding walks can coexist. At these temperatures, ensemble averages over coexisting states give rise to statistics that resemble ideal chains without there being an actual counterbalancing of intra-chain and chain-solvent interactions. At equivalent temperatures, arginine-rich sequences tilt the preference toward globular conformations whereas lysine-rich sequences tilt the preference toward self-avoiding walks. This stems from intrinsic differences in free energies of hydration between arginine and lysine. We also identify differences between aspartate and glutamate containing sequences, whereby the shorter aspartate sidechain engenders preferences for metastable, necklace-like conformations. Finally, although segregation of oppositely charged residues within the linear sequence maintains the overall two-state behavior, compact states are highly favored by such systems.

scholarly journals Ion Mobility Mass Spectrometry Uncovers the Impact of the Patterning of Oppositely Charged Residues on the Conformational Distributions of Intrinsically Disordered Proteins

2018 ◽  
Author(s):  
Rebecca Beveridge ◽  
Lukasz Migas ◽  
Rahul Das ◽  
Rohit Pappu ◽  
Richard Kriwacki ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ion Mobility ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Ion Mobility Mass Spectrometry ◽  
Conformational Heterogeneity ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Charged Residues ◽  
Oppositely Charged

The global dimensions and amplitudes of conformational fluctuations of intrinsically disordered proteins are governed, in part, by the linear segregation versus clustering of oppositely charged residues within the primary sequence. Ion Mobility-Mass Spectrometry (IM-MS) affords unique advantages for probing the conformational consequences of the linear patterning of oppositely charged residues because it measures and separates proteins electrosprayed from solution on the basis of charge and shape. Here, we use IM-MS to measure the conformational consequences of charge patterning on the C-terminal intrinsically disordered region (p27 IDR) of the cell cycle inhibitory protein p27<sup>Kip1</sup>. We report the range of charge states and accompanying collisional cross section distributions for wild-type p27 IDR and two variants with identical amino acid compositions, k14 and k56, distinguished by the extent of linear mixing versus segregation of oppositely charged residues. Wild-type p27 IDR (k31) and k14 where the oppositely charged residues are more evenly distributed, exhibit a broad distribution of charge states. This is concordant with high degrees of conformational heterogeneity in solution. By contrast, k56 with linear segregation of oppositely charged residues, leads to limited conformational heterogeneity and a narrow distribution of charged states. Molecular dynamics simulations demonstrate that the interplay between chain solvation and intra-chain interactions (self-solvation) leads to conformational distributions that are modulated by salt concentration, with the wild-type sequence showing the most sensitivity to changes in salt concentration. These results suggest that the charge patterning within the wild-type p27 IDR may be optimized to sample both highly solvated and self-solvated conformational states.

scholarly journals Ion Mobility Mass Spectrometry Uncovers the Impact of the Patterning of Oppositely Charged Residues on the Conformational Distributions of Intrinsically Disordered Proteins

2018 ◽  
Author(s):  
Rebecca Beveridge ◽  
Lukasz Migas ◽  
Rahul Das ◽  
Rohit Pappu ◽  
Richard Kriwacki ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ion Mobility ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Ion Mobility Mass Spectrometry ◽  
Conformational Heterogeneity ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Charged Residues ◽  
Oppositely Charged

The global dimensions and amplitudes of conformational fluctuations of intrinsically disordered proteins are governed, in part, by the linear segregation versus clustering of oppositely charged residues within the primary sequence. Ion Mobility-Mass Spectrometry (IM-MS) affords unique advantages for probing the conformational consequences of the linear patterning of oppositely charged residues because it measures and separates proteins electrosprayed from solution on the basis of charge and shape. Here, we use IM-MS to measure the conformational consequences of charge patterning on the C-terminal intrinsically disordered region (p27 IDR) of the cell cycle inhibitory protein p27<sup>Kip1</sup>. We report the range of charge states and accompanying collisional cross section distributions for wild-type p27 IDR and two variants with identical amino acid compositions, k14 and k56, distinguished by the extent of linear mixing versus segregation of oppositely charged residues. Wild-type p27 IDR (k31) and k14 where the oppositely charged residues are more evenly distributed, exhibit a broad distribution of charge states. This is concordant with high degrees of conformational heterogeneity in solution. By contrast, k56 with linear segregation of oppositely charged residues, leads to limited conformational heterogeneity and a narrow distribution of charged states. Molecular dynamics simulations demonstrate that the interplay between chain solvation and intra-chain interactions (self-solvation) leads to conformational distributions that are modulated by salt concentration, with the wild-type sequence showing the most sensitivity to changes in salt concentration. These results suggest that the charge patterning within the wild-type p27 IDR may be optimized to sample both highly solvated and self-solvated conformational states.

scholarly journals Intrinsically disordered caldesmon binds calmodulin via the “buttons on a string” mechanism

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1265 ◽  
Author(s):  
Sergei E. Permyakov ◽  
Eugene A. Permyakov ◽  
Vladimir N. Uversky
Keyword(s):  
Local Structure ◽  
Intrinsically Disordered Proteins ◽  
String Model ◽  
Electrostatic Attraction ◽  
Disordered Proteins ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Tryptophan Residues ◽  
Specific Packing ◽  
Oppositely Charged

We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636–771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be described as the “buttons on a charged string” model, where the electrostatic attraction between the intrinsically disordered CaD136and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD136“pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD136-CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD136-CaM binding and since CaD136remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.

scholarly journals The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins

2021 ◽  
Vol 22 (20) ◽  
pp. 11058
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Intrinsically Disordered ◽  
Local Contraction ◽  
Charged Residues ◽  
Common Strategy ◽  
Disordered Peptides ◽  
Dynamics Simulations ◽  
The Impact

Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation.

scholarly journals Does intrinsically disordered caldesmon bind calmodulin via the “buttons on a string” mechanism?

2015 ◽  
Author(s):  
Sergei E Permyakov ◽  
Eugene A Permyakov ◽  
Vladimir N Uversky
Keyword(s):  
Local Structure ◽  
Intrinsically Disordered Proteins ◽  
String Model ◽  
Electrostatic Attraction ◽  
Disordered Proteins ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Tryptophan Residues ◽  
Specific Packing ◽  
Oppositely Charged

We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be described as the “buttons on a charged string” model, where the electrostatic attraction between the intrinsically disordered CaD136 and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD136 “pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD136-CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD136-CaM binding and since CaD136 remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.

scholarly journals Salt-bridge Dynamics in Intrinsically Disordered Proteins: A trade-off between electrostatic interactions and structural flexibility

2017 ◽  
Author(s):  
Sankar Basu ◽  
Parbati Biswas
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Salt Bridge ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Trade Off ◽  
Local Rigidity ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Oppositely Charged

AbstractIntrinsically Disordered Proteins (IDPs) are enriched in charged and polar residues; and, therefore, electrostatic interactions play a predominant role in their dynamics. In order to remain multi-functional and exhibit their characteristic binding promiscuity, they need to retain considerable dynamic flexibility. At the same time, they also need to accommodate a large number of oppositely charged residues, which eventually lead to the formation of salt-bridges, imparting local rigidity. The formation of salt-bridges therefore oppose the desired dynamic flexibility. Hence, there appears to be a meticulous trade-off between the two mechanisms which the current study attempts to unravel. With this objective, we identify and analyze salt-bridges, both as isolated as well as composite ionic bond motifs, in the molecular dynamic trajectories of a set of appropriately chosen IDPs. Time evolved structural properties of these salt-bridges like persistence, associated secondary structural ′order-disorder′ transitions, correlated atomic movements, contribution in the overall electrostatic balance of the proteins have been studied in necessary detail. The results suggest that the key to maintain such a trade-off over time is the continuous formation and dissolution of salt-bridges with a wide range of persistence. Also, the continuous dynamic interchange of charged-atom-pairs (coming from a variety of oppositely charged side-chains) in the transient ionic bonds supports a model of dynamic flexibility concomitant with the well characterized stochastic conformational switching in these proteins. The results and conclusions should facilitate the future design of salt-bridges as a mean to further explore the disordered-globular interface in proteins.

scholarly journals Does intrinsically disordered caldesmon bind calmodulin via the “buttons on a string” mechanism?

2015 ◽  
Author(s):  
Sergei E Permyakov ◽  
Eugene A Permyakov ◽  
Vladimir N Uversky
Keyword(s):  
Local Structure ◽  
Intrinsically Disordered Proteins ◽  
String Model ◽  
Electrostatic Attraction ◽  
Disordered Proteins ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Tryptophan Residues ◽  
Specific Packing ◽  
Oppositely Charged

We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be described as the “buttons on a charged string” model, where the electrostatic attraction between the intrinsically disordered CaD136 and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD136 “pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD136-CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD136-CaM binding and since CaD136 remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.

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