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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.
Acknowledgements
Supported by a gift from Mr. David Koch (P.K.), and a National Science Foundation Graduate Research Fellowship (G.M.). G.R. was supported by grants from J.C. Bose National Fellowship, DST Center for Mathematical Biology, DST IRHPA Centre for Neuroscience and UGC Centre for Advanced Studies. G.R. is an Honorary Professor at the Jawaharlal Nehru Centre for Advanced Scientific Research. The authors would like to thank Dr. Robert Veltri and Dr. Donald Coffey, Dr. Vidyanand Nanjundiah and Dr. S Mahadevan for their thoughtful comments, Dr. Steve Mooney for critically reading, Mr. David Yeater for his expert help in editing the manuscript and Prof. Ozlem Keskin for the cancer network data. P.K. is indebted to Dr. Amita Behal for very fruitful discussions on the subject. G.R. would like to thank Dr. Sitabhra Sinha and Mr. Tomás Di Domenico for their inputs on network modeling and detection of disordered proteins, respectively.
