Intrinsically disordered proteins and conformational noise: The hypothesis a decade later

Kulkarni, Prakash; Salgia, Ravi; Rangarajan, Govindan

doi:10.1016/j.isci.2023.107109

Cited by 7 publications

(8 citation statements)

References 81 publications

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“…These interactions lead to the activation of latent pathways by rewiring the PIN to yield a new PIN configuration that produces the optimal output, underscoring the critical role of IDPs in regulating information flow ( Figure 2 ). Indeed, evidence accumulated to date lends further credence to this hypothesis as well as providing a conceptual framework to explain how IDP conformational dynamics and conformational noise impact cellular decision-making [ 2 , 17 , 56 , 57 ].…”

Section: Intrinsically Disordered Proteins Conformational Noise and P...mentioning

confidence: 99%

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Ramisetty,

Subbalakshmi,

Pareek

et al. 2024

JCM

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Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

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Section: Intrinsically Disordered Proteins Conformational Noise and P...mentioning

confidence: 99%

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Ramisetty,

Subbalakshmi,

Pareek

et al. 2024

JCM

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“…The protein–protein interactions (PPIs) mediated by intrinsic disorder play a critical role in cell signaling (Bondos et al, 2022; Dunker et al, 2005; Iakoucheva et al, 2002; Uversky et al, 2005), allostery (Berlow et al, 2018; Eginton et al, 2015; Ferreon et al, 2013; Garcia‐Pino et al, 2010; Hilser & Thompson, 2011; Huang et al, 2020; Li & Hilser, 2018; Motlagh et al, 2012, 2015; Motlagh & Hilser, 2012; Tee et al, 2020; Tompa, 2014; Wrabl et al, 2011), and can act as molecular switches (Berlow et al, 2022; Choi et al, 2019; Dennis, 2015; Hong et al, 2020; Kulkarni et al, 2018, 2023; Kulkarni & Kulkarni, 2019; Lin et al, 2019; Salladini et al, 2020; Taylor et al, 2019, 2021; van Roey et al, 2012). The short lifetimes and reversible nature of the complexes formed by IDPs/IDRs with partnering proteins have been discussed at length earlier by one of us (Uversky, 2020b).…”

Section: Interactions Of Idps/idrs With Other Proteins and Surfaces I...mentioning

confidence: 99%

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Gupta,

Uversky

2024

Protein Science

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The rationale for replacing the old binary of structure–function with the trinity of structure, disorder, and function has gained considerable ground in recent years. A continuum model based on the expanded form of the existing paradigm can now subsume importance of both conformational flexibility and intrinsic disorder in protein function. The disorder is actually critical for understanding the protein–protein interactions in many regulatory processes, formation of membrane‐less organelles, and our revised notions of specificity as amply illustrated by moonlighting proteins. While its importance in formation of amyloids and function of prions is often discussed, the roles of intrinsic disorder in infectious diseases and protein function under extreme conditions are also becoming clear. This review is an attempt to discuss how our current understanding of protein function, specificity, and evolution fit better with the continuum model. This integration of structure and disorder under a single model may bring greater clarity in our continuing quest for understanding proteins and molecular mechanisms of their functionality.

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“…More than a decade ago, the conformational noise hypothesis was enunciated describing how noise emanating from conformational dynamics of intrinsically disordered proteins (IDPs) which is distinct from transcriptional noise, can contribute to phenotypic switching and hence, phenotypic plasticity, by rewiring the cellular protein interaction network. 2 , 3 Since most transcription factors are IDPs, it was posited that conformational noise is an integral component of transcriptional noise implying that IDPs may amplify total noise in the system either stochastically or in response to environmental changes. This concept helped lay the foundation for the genetic/non-genetic duality elaborated by Salgia and Kulkarni 4 which is now well accepted in the field.…”

Section: Main Textmentioning

confidence: 99%

“… 11 However, such approaches have also revealed that phenotypic plasticity can result from non-genetic perturbations that include transcriptional and protein conformational noise, especially from IDPs that occupy key positions in cellular protein interaction networks, as well as from epigenetic modifications. 3 …”

Section: Main Textmentioning

confidence: 99%

Comprehending phenotypic plasticity in cancer and evolution

Kulkarni,

Salgia

2024

iScience

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Intrinsically disordered proteins and conformational noise: The hypothesis a decade later

Cited by 7 publications

References 81 publications

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Comprehending phenotypic plasticity in cancer and evolution

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