Intrinsically Disordered Proteins Display No Preference for Chaperone Binding In Vivo

Hedi Hegyi,Peter Tompa,Paul Harrison

doi:10.1371/journal.pcbi.1000017

Abstract

Intrinsically disordered/unstructured proteins (IDPs) are extremely sensitive to proteolysis in vitro, but show no enhanced degradation rates in vivo. Their existence and functioning may be explained if IDPs are preferentially associated with chaperones in the cell, which may offer protection against degradation by proteases. To test this inference, we took pairwise interaction data from high-throughput interaction studies and analyzed to see if predicted disorder correlates with the tendency of chaperone binding by proteins. Our major finding is that disorder predicted by the IUPred algorithm actually shows negative correlation with chaperone binding in E. coli, S. cerevisiae, and metazoa species. Since predicted disorder positively correlates with the tendency of partner binding in the interactome, the difference between the disorder of chaperone-binding and non-binding proteins is even more pronounced if normalized to their overall tendency to be involved in pairwise protein–protein interactions. We argue that chaperone binding is primarily required for folding of globular proteins, as reflected in an increased preference for chaperones of proteins in which at least one Pfam domain exists. In terms of the functional consequences of chaperone binding of mostly disordered proteins, we suggest that its primary reason is not the assistance of folding, but promotion of assembly with partners. In support of this conclusion, we show that IDPs that bind chaperones also tend to bind other proteins.

Highlights

Disordered/unstructured proteins or protein domains (IDPs) are prevalent in proteomes [1,2,3] due to the inherent functional advantages structural disorder imparts on proteins [1,4,5,6]
These and other functional features explain a high level of disorder in important regulatory proteins involved in signaling, and regulation of transcription, such as p53 [7], p27Kip1 [8], CREB [9] or BRCA1 [10]. Whereas these features elucidate the prevalence of protein disorder in proteomes underlying the recent heightened interest in the subject, the phenomenon of structural disorder poses further serious questions. Due to their open and flexible conformational state, Intrinsically disordered/unstructured proteins (IDPs) are exceptionally sensitive to proteolysis in vitro [4,11], which raises concerns in terms of their in vivo existence and functioning
Disordered/unstructured proteins (IDPs) defy the classical structure–function paradigm because they exist and function without a well-defined 3-D structure. These proteins are extremely sensitive to degradation in the test tube, but show no enhanced degradation rates in the cell. To resolve this apparent contradiction, we tested whether IDPs are protected by interaction with accessory proteins, chaperones, often implicated in guarding other proteins in the cell

Summary

Introduction

Disordered/unstructured proteins or protein domains (IDPs) are prevalent in proteomes [1,2,3] due to the inherent functional advantages structural disorder imparts on proteins [1,4,5,6]. IDPs have been noted for an increased speed of interaction, specificity without excessive binding strength, adaptability to multiple partners and ease of regulation by post-translational modification These and other functional features explain a high level of disorder in important regulatory proteins involved in signaling, and regulation of transcription, such as p53 [7], p27Kip1 [8], CREB [9] or BRCA1 [10]. The question most often asked is how IDPs function when they are supposedly rapidly degraded by proteases in vivo That this is not the case, is shown by our recent observations that the physiological half-lives of IDPs determined in a high-throughput study [12] show very weak correlation with their disorder content [13]. Since chaperone action has already been implicated with some IDPs [14,15,16], we have decided to analyze recent high-throughput interaction data to provide a systematic and coherent answer to this question

Methods

Results

Discussion

Conclusion