Intrinsically disordered proteins and conformational noise Implications in cancer

Gita Mahmoudabadi, Krithika Rajagopalan, Robert H. Getzenberg, Sridhar Hannenhalli, Govindan Rangarajan, Prakash Kulkarni

Research output: Contribution to journalArticle

Abstract

Intrinsically disordered proteins, IDPs, are proteins that lack a rigid 3D structure under physiological conditions, at least in vitro. Despite the lack of structure, IDPs play important roles in biological processes and transition from disorder to order upon binding to their targets. With multiple conformational states and rapid conformational dynamics, they engage in myriad and often "promiscuous" interactions. These stochastic interactions between IDPs and their partners, defined here as conformational noise, is an inherent characteristic of IDP interactions. The collective effect of conformational noise is an ensemble of protein network configurations, from which the most suitable can be explored in response to perturbations, conferring protein networks with remarkable flexibility and resilience. Moreover, the ubiquitous presence of IDPs as transcriptional factors and, more generally, as hubs in protein networks, is indicative of their role in propagation of transcriptional (genetic) noise. As effectors of transcriptional and conformational noise, IDPs rewire protein networks and unmask latent interactions in response to perturbations. Thus, noise-driven activation of latent pathways could underlie state-switching events such as cellular transformation in cancer. To test this hypothesis, we created a model of a protein network with the topological characteristics of a cancer protein network and tested its response to a perturbation in presence of IDP hubs and conformational noise. Because numerous IDPs are found to be epigenetic modifiers and chromatin remodelers, we hypothesize that they could further channel noise into stable, heritable genotypic changes.

Original languageEnglish (US)
Pages (from-to)26-31
Number of pages6
JournalCell Cycle
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Cancer
  • Evolution
  • Intrinsically disordered proteins
  • Noise
  • Protein-protein interaction network
  • State-switching

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Intrinsically disordered proteins and conformational noise Implications in cancer'. Together they form a unique fingerprint.

  • Cite this

    Mahmoudabadi, G., Rajagopalan, K., Getzenberg, R. H., Hannenhalli, S., Rangarajan, G., & Kulkarni, P. (2013). Intrinsically disordered proteins and conformational noise Implications in cancer. Cell Cycle, 12(1), 26-31. https://doi.org/10.4161/cc.23178