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Another Window into Disordered Protein Function

2007; Elsevier BV; Volume: 15; Issue: 9 Linguagem: Inglês

10.1016/j.str.2007.08.001

1878-4186

A. Keith Dunker,

RNA and protein synthesis mechanisms

Multiple crystal structures of the same proteins often have specific regions that switch between structure and disorder. In this issue of Structure, Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar show that these "dual personality fragments" are distinct from both structured and disordered protein and are functionally important. Multiple crystal structures of the same proteins often have specific regions that switch between structure and disorder. In this issue of Structure, Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar show that these "dual personality fragments" are distinct from both structured and disordered protein and are functionally important. Current biochemistry textbooks discuss the typical functions of globular proteins in terms of "lock and key" and "induced fit" models. The lock and key model depends on a structured protein with a rigid binding site, while the original induced fit model was described in terms of a structured protein with a flexible binding site that undergoes conformational change upon interaction with its ligand. Induced fit was later extended to include binding site changes resulting from domain shifts. For both the lock and key and the induced fit models, the formation of protein 3D structure is a prerequisite to function and can be described as the sequence → structure → function paradigm. While still not discussed in biochemistry textbooks, another model for globular protein function has been in the focus of active theoretical and experimental research for a long time. In this alternative model, the protein starts as an interconverting ensemble under physiological conditions, a state that has been called "natively unfolded" (Weinreb et al., 1996Weinreb P.H. Zhen W. Poon A.W. Conway K.A. Lansbury Jr., P.T. Biochemistry. 1996; 35: 13709-13715Crossref PubMed Scopus (1318) Google Scholar), "intrinsically unstructured" (Wright and Dyson, 1999Wright P.E. Dyson H.J. J. Mol. Biol. 1999; 293: 321-331Crossref PubMed Scopus (2335) Google Scholar), and "disordered" coupled with various adjectives. Different functions, such as molecular recognition, occur as the disordered protein undergoes coupled binding and folding. A number of prior studies focused on the prediction of disordered regions in a protein (Ferron et al., 2006Ferron F. Longhi S. Canard B. Karlin D. Proteins. 2006; 65: 1-14Crossref PubMed Scopus (231) Google Scholar). Within a given protein sequence, local features suggesting increased tendency for order often correlate with binding sites within the disordered regions (Figures 1A and 1B). However, other binding sites don't exhibit this correlation with regions that have greater tendency to be structured (Figures 1C and 1D). Those binding sites that show a tendency for order typically form helix or sheet upon binding, while the other binding sites, in regions that lack obvious tendencies to form structure, typically assume random structures upon binding and are often rich in proline. The obvious dips in the disorder prediction plots provided the starting point for predictors of binding sites, which were called "molecular recognition features" or "MoRFs" (Oldfield et al., 2005Oldfield C.J. Cheng Y. Cortese M.S. Romero P. Uversky V.N. Dunker A.K. Biochemistry. 2005; 44: 12454-12470Crossref PubMed Scopus (534) Google Scholar). MoRF predictions have been used to guide experiments that successfully led to the identification of binding segments within disordered regions (Bourhis et al., 2004Bourhis J.M. Johansson K. Receveur-Brechot V. Oldfield C.J. Dunker K.A. Canard B. Longhi S. Virus Res. 2004; 99: 157-167Crossref PubMed Scopus (147) Google Scholar). Both dip-associated binding sites and binding sites without the corresponding dips could potentially be identified by the colocalization of a disorder prediction and a specific binding motif. Many disordered regions form associations with multiple, distinct partners. While structural information is not always available, in several examples the secondary structure was found to depend on the partner rather than being an innate property of the sequence within the disordered region. For example, the same short region near the disordered N terminus of p53 forms a helix with one partner, a sheet with a second partner, and two different irregular structures with two other partners (Oldfield et al., 2007Oldfield, C.J., Meng, J., Yang, J.Y., Uversky, V.N., and Dunker, A.K. (2007). Proceedings of the BioComp '07 Meeting, in press.Google Scholar). When experimentally characterized regions of disorder were examined by literature searches for evidence of function, such regions were commonly found to undergo posttranslational modifications (Dunker et al., 2002Dunker A.K. Brown C.J. Lawson J.D. Iakoucheva L.M. Obradovic Z. Biochemistry. 2002; 41: 6573-6582Crossref PubMed Scopus (1489) Google Scholar), and bioinformatics analysis recently identified 238 SwissProt functional key words likely associated with disordered regions of proteins, including many types of posttranslational modifications (Xie et al., 2007Xie H. Vucetic S. Iakoucheva L.M. Oldfield C.J. Dunker A.K. Uversky V.N. Obradovic Z. J. Proteome Res. 2007; 6: 1882-1898Crossref PubMed Scopus (447) Google Scholar). Against this background of recent studies on the functions and structural transitions of disordered proteins and regions, Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar carried out a new and clever investigation of disordered protein regions that have the ability to become structured under some conditions. Specifically, they identified segments observed to be structured in one protein crystal, but to be unobserved or disordered in a different crystal of the same protein. In our survey of disorder in the Protein Data Bank, we noticed this same phenomenon (Le Gall et al., 2007Le Gall T. Romero P. Cortese M.S. Uversky V.N. Dunker A.K. J. Biomol. Struct. Dyn. 2007; 24: 324-342Google Scholar), but we did not specifically focus our attention on these very interesting regions. Two main findings in Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar are: (1) these regions, termed "dual personality fragments," have amino acid compositions between those of a collection of structured proteins and those of a collection of disordered proteins, and (2) functions are often localized within these dual personality fragments with evidence of posttranslational modification frequently observed. The dual personality fragments undergo intramolecular transitions between structure and disorder in the different crystal forms of the same protein. Our studies on MoRFs emphasized intermolecular rather than intramolecular interactions. The predictor used for Figure 1 is based on discriminating structure-associated amino acid compositions from disorder-associated amino acid compositions. The intermediate values predicted for MoRFs indicate that these segments likely have amino acid compositions between those of typical structured and disordered proteins. Thus, MoRFs and dual personality fragments, both of which switch between structure and disorder, likely have similar compositions. Comparing the amino acid compositions of dual personality fragments with the compositions of a collection of MoRFs would be a useful exercise. A basic question is whether any disordered region can undergo a disorder-to-order transition if the right partner is present to induce the folding. Alternatively, perhaps some disordered regions are simply incapable of undergoing induced folding no matter what partner is nearby. Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar show that some disordered regions fail to form structure over multiple, different crystal structures, while other regions are structured in one or more crystals and unstructured in one or more different crystals. A simple inference from these observations is that some disordered sequences are capable of becoming structured with the right partners while others are not (or are much less capable of forming structure). On the other hand, the capacity of the same region to form helix, sheet, or coil, depending on the partner (Oldfield et al., 2007Oldfield, C.J., Meng, J., Yang, J.Y., Uversky, V.N., and Dunker, A.K. (2007). Proceedings of the BioComp '07 Meeting, in press.Google Scholar), and the ability of highly disordered regions to form structure, like the disordered region in Figures 1C and 1D, both suggest that the partner is especially important for inducing structure. These latter results support the possibility that any disordered region can form structure in the presence of the right partner. Overall, the Zhang et al., 2007Zhang Y. Stec B. Godzik A. Structure. 2007; 15 (this issue): 1141-1147Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar paper suggests a new approach for putting disordered regions into different categories that differ in their tendencies to form structure. Further work to classify different regions of disorder into different categories can only help to increase our understanding of these interesting proteins and regions. Between Order and Disorder in Protein Structures: Analysis of "Dual Personality" Fragments in ProteinsZhang et al.StructureSeptember 11, 2007In BriefIn their natural environment, three-dimensional structures of proteins undergo significant fluctuations and are often partially or completely disordered. This phenomenon recently became the focus of much attention, as many proteins, especially from higher organisms, were shown to contain large intrinsically disordered regions. Such disordered regions may become ordered only under very specific circumstances, if at all, and can be recognized by specific amino acid composition and sequence signatures. Full-Text PDF Open Archive