Folded domain charge properties influence the conformational behavior of disordered tails

Taneja, Ishan; Holehouse, Alex S.

doi:10.1016/j.crstbi.2021.08.002

Cited by 35 publications

(23 citation statements)

References 79 publications

(112 reference statements)

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“…This is because the interactions between oppositely charged blocky residues within the CTT are stronger than CTT-core interactions as κ +- increases beyond 0.41. This observation is supported by results from previous studies for other systems (8, 73).…”

Section: Resultssupporting

confidence: 91%

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Connecting sequence features within the disordered C-terminal linker ofB. subtilisFtsZ to functions and bacterial cell division

Shinn

Cohan²,

Bullock

et al. 2022

Preprint

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Intrinsically disordered regions (IDRs) can function as autoregulators of folded enzymes to which they are tethered. One example of such a system is the protein FtsZ that controls cell division in bacteria. FtsZs include a folded core and a C-terminal tail (CTT). The latter encompasses a poorly conserved, disordered C-terminal linker (CTL) and a well-conserved 17-residue C-terminal peptide (CT17). Sites for GTPase activity of FtsZs are formed at the interface between GTP binding sites and T7 loops on cores of adjacent subunits within dimers. Here, we explore the basis of autoregulatory functions of the CTL plus CT17 in Bacillus subtilis FtsZ (Bs-FtsZ). Molecular simulations show that the CT17 of Bs-FtsZ makes statistically significant CTL-mediated contacts with the T7 loop. To test how CTL-mediated CT17-core contacts modulate subunit interactions and GTP hydrolysis, we designed Bs-FtsZ variants where we altered the patterning of oppositely charged residues within the CTL and assessed the effects on FtsZ assembly and function. Increasing the linear segregation of oppositely charged residues within the CTL disrupts core-CTT interactions. Mutations that enhance cohesive interactions among CTTs lead to alternative, tail-driven assemblies that diminish enzymatic activity. Altering the linear segregation of oppositely charged residues within the CTL can lead to protein degradation, aberrant assembly, and disruption of cell division in vivo. The functionally relevant non-random sequence patterns identified in this work are conserved across CTLs from orthologs. Our findings highlight how sequence patterns that contribute to functions can be uncovered in IDRs, including those with minimal sequence conservation.Significance StatementConserved sequence-structure-function relationships are the defining hallmarks of well-folded proteins. These relationships can be gleaned by combining multiple sequence alignments with covariation analyses. However, the approaches that work for well-folded proteins are not transferable to intrinsically disordered regions (IDRs) because their sequences vary dramatically across orthologs. Here, we use the C-terminal autoregulatory tail (CTT) of the bacterial cell division protein FtsZ to prototype a multi-pronged approach for studying IDRs. We show how non-random sequence patterns within IDRs can be uncovered, analyzed for conservation, and redesigned to unmask their impact on molecular functions and cellular phenotypes. Through our work, we also introduce multi-pronged approaches that combine biophysical computations and biochemical experiments to understand how the CTT, as an IDR, functions.

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Section: Resultssupporting

confidence: 91%

“…O interactions as κ+-increases beyond 0.41. This observation is supported by results from previous studies for other systems (8,73).…”

Section: Increasing κ+-Of the Ctt Introduces Intra-ctt Interactions A...supporting

confidence: 91%

Connecting sequence features within the disordered C-terminal linker ofB. subtilisFtsZ to functions and bacterial cell division

Shinn

Cohan²,

Bullock

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Such transitions, especially in the context of tethered systems, are likely to make important contributions to the spatial and temporal control over biochemical reactions where IDRs modulate the effective concentrations of ligands around binding sites or of substrates around active sites of enzymes ( 31 , 32 , 34 , 57 , 101 – 105 ). While our results are presented for IDRs studied as autonomous units, we expect that our findings will be transferable to tethered IDRs, albeit with context-dependent modifications ( 103 , 106 ).…”

Section: Discussionmentioning

confidence: 79%

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

Zeng

Ruff

Pappu

2022

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

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Significance Intrinsically disordered regions (IDRs) of proteins, when tethered to folded domains, function either as flexible tails or as linkers between domains. Most IDRs are polyampholytes that comprise a mixture of oppositely charged residues. Recent measurements of tethered polyampholytes showed the tendency of arginine- and lysine-rich sequences to behave very differently from one another. Using computer simulations, we show that these differences are determined by differences in free energies of hydration, steric volumes, and other considerations. Further, the interplay between electrostatic attractions and favorable free energies of hydration creates distinct stable states for polyampholytic IDRs. These findings have implications for switch-like transitions and the regulation of effective concentrations of interaction motifs by IDRs.

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“…Such transitions, especially in the context of tethered systems, are likely to make important contributions to the spatial and temporal control over biochemical reactions where IDRs modulate the effective concentrations of ligands around binding sites or of substrates around active sites of enzymes (31, 32, 34, 57, 101-105). While our results are presented for IDRs studied as autonomous units, we expect that our findings will be transferable to tethered IDRs, albeit with context-dependent modifications (103, 106).…”

Section: Discussionmentioning

confidence: 79%

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

Zeng

Ruff

Pappu

2022

Preprint

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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.

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Folded domain charge properties influence the conformational behavior of disordered tails

Cited by 35 publications

References 79 publications

Connecting sequence features within the disordered C-terminal linker ofB. subtilisFtsZ to functions and bacterial cell division

Connecting sequence features within the disordered C-terminal linker ofB. subtilisFtsZ to functions and bacterial cell division

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

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

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