Sequence determinants of compaction in intrinsically disordered proteins.
Intrinsically disordered proteins (IDPs), which lack folded structure and are disordered under nondenaturing conditions, have been shown to perform important functions in a large number of cellular processes. These proteins have interesting structural properties that deviate from the random-coil-like behavior exhibited by chemically denatured proteins. In particular, IDPs are often observed to exhibit significant compaction. In this study, we have analyzed the hydrodynamic radii of a number of IDPs to investigate the sequence determinants of this compaction. Net charge and proline content are observed to be strongly correlated with increased hydrodynamic radii, suggesting that these are the dominant contributors to compaction. Hydrophobicity and secondary structure, on the other hand, appear to have negligible effects on compaction, which implies that the determinants of structure in folded and intrinsically disordered proteins are profoundly different. Finally, we observe that polyhistidine tags seem to increase IDP compaction, which suggests that these tags have significant perturbing effects and thus should be removed before any structural characterizations of IDPs. Using the relationships observed in this analysis, we have developed a sequence-based predictor of hydrodynamic radius for IDPs that shows substantial improvement over a simple model based upon chain length alone.
Marsh
Joseph A
JA
Molecular Structure and Function, Hospital for Sick Children, and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Forman-Kay
Julie D
JD
D019295:Computational Biology; D006639:Histidine / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D011392:Proline / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
D011506:Proteins; C033223:polyhistidine; D006639:Histidine; D011392:Proline