Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins

Abstract

Transcription factors and other allosteric cell signaling proteins contain a disproportionate number of domains or segments that are intrinsically disordered (ID) under native conditions. In many cases folding of these segments is coupled to binding with one or more of their interaction partners, suggesting that intrinsic disorder plays an important functional role. Despite numerous hypotheses for the role of ID domains in regulation, a mechanistic model has yet to be established that can quantitatively assess the importance of intrinsic disorder for intramolecular site-to-site communication, the hallmark property of allosteric proteins. Here, we present such a model and show that site-to-site allosteric coupling is maximized when intrinsic disorder is present in the domains or segments containing one or both of the coupled binding sites. This result not only explains the prevalence of ID domains in regulatory proteins, it also calls into question the classical mechanical view of energy propagation in proteins, which predicts that site-to-site coupling would be maximized when a well defined pathway of folded structure connects the two sites. Furthermore, in showing that the coupling mechanism conferred by intrinsic disorder is robust and independent of the network of interactions that physically link the coupled sites, unique insights are gained into the energetic ground rules that govern site-to-site communication in all proteins.allostery ͉ ensemble ͉ regulation ͉ site-to-site communication O ver the past decade, the paradigm that proteins function by adopting highly ordered structures has been challenged by the observation that thousands of different proteins are likely to be intrinsically disordered (i.e., sample multiple conformations) or have intrinsically disordered (ID) domains under native conditions (1-8). Of particular significance is the growing body of evidence that intrinsic disorder is found in disproportionately higher amounts in cell signaling proteins and transcription factors, suggesting an important role in their regulatory capacity (5). Indeed for cases where detailed study has been performed, structure formation in these proteins (or domains) is linked to ligand binding in other parts of the molecule, indicating that the order/disorder transition is coupled to long-range allosteric communication within the molecule and is therefore important to its functional role (5). Interestingly, within specific classes of regulatory proteins [such as the steroid hormone receptors (9)], functionally analogous domains relevant to transcription regulation appear to be ID in each member, even though there is little sequence conservation in these regions. This finding suggests that the underlying regulatory mechanism is both effective and robustly encoded in nature.Hypotheses for the role of intrinsic disorder include: highspecificity/low-affinity binding (3, 5), rapid protein turnover (1), and high specificity for multiple targets (1-5). However, despite the clear experimental evidence for the existence of...

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