From Sequence and Forces to Structure, Function, and Evolution of Intrinsically Disordered Proteins
2013; Elsevier BV; Volume: 21; Issue: 9 Linguagem: Inglês
10.1016/j.str.2013.08.001
ISSN1878-4186
AutoresJulie D. Forman‐Kay, Tanja Mittag,
Tópico(s)RNA and protein synthesis mechanisms
ResumoIntrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics, and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales, and compactness are shaping a unified understanding of structure-dynamics-disorder/function relationships. In the 20th anniversary of Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional, and evolutionary properties. Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics, and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales, and compactness are shaping a unified understanding of structure-dynamics-disorder/function relationships. In the 20th anniversary of Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional, and evolutionary properties. One view of the overall goal of structural biology is to provide insights into the physical chemistry of biological function. This entails descriptions of the free energy landscapes of all relevant macromolecules in isolation and in their interactions to predict the kinetics and thermodynamics underlying conformational states, catalytic reactions, and binding properties. Such a goal is extremely challenging and many structural biologists have been satisfied by characterizations of the low energy wells on the energy landscapes of macromolecules and some limited numbers of combinations of macromolecules. This less ambitious scope has provided powerful correlations between structural properties of folded macromolecules and complexes and their biological functions. Thus, the broader goal has been thought by many to be superseded. However, it is becoming increasingly apparent that biological function utilizes higher energy states of folded macromolecules (Baldwin and Kay, 2009Baldwin A.J. Kay L.E. NMR spectroscopy brings invisible protein states into focus.Nat. Chem. Biol. 2009; 5: 808-814Crossref PubMed Scopus (146) Google Scholar, Clore, 2011Clore G.M. Exploring sparsely populated states of macromolecules by diamagnetic and paramagnetic NMR relaxation.Protein Sci. 2011; 20: 229-246Crossref PubMed Scopus (31) Google Scholar, Osawa et al., 2012Osawa M. 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Biol. 2011; 8: 035003Crossref Scopus (25) Google Scholar). Proteins with this latter nature have been called intrinsically disordered because they do not adopt unique, well-folded three-dimensional structures but rather populate ensembles of diverse, interconverting conformations. Note that these ensembles, while lacking persistent structure, are "stable" in the thermodynamic sense. This means that the dynamic equilibrium of distinct conformations (i.e., disorder), with its significant conformational entropy, is lower in free energy under the prevailing conditions than a single conformation or narrow distribution of conformations. Intrinsically disordered proteins represent a significant challenge to the previously described body of structure/function correlations. However, from the standpoint of physical chemistry, it should not be surprising that all available energetic possibilities and all accessible conformations can be exploited for various functional purposes. In this regard, a powerful view that includes the entire continuum of dynamic and energetic properties of proteins as well as monomer, oligomer, and higher order assemblies is emerging. Interestingly, prior to the 1957 pioneering work on the binding of the S-protein and S-peptide of cleaved RNase A (Richards, 1997Richards F.M. Whatever happened to the fun? An autobiographical investigation.Annu. Rev. Biophys. Biomol. Struct. 1997; 26: 1-25Crossref PubMed Scopus (7) Google Scholar) and, shortly thereafter, the first crystal structures of ordered proteins (Kendrew et al., 1960Kendrew J.C. Dickerson R.E. Strandberg B.E. Hart R.G. Davies D.R. Phillips D.C. Shore V.C. Structure of myoglobin: A three-dimensional Fourier synthesis at 2 A. resolution.Nature. 1960; 185: 422-427Crossref PubMed Scopus (456) Google Scholar), which demonstrated that proteins can be ordered in three dimensions with tight intramolecular interactions, all proteins were thought of as highly malleable. The notion of proteins having similar structural and dynamic properties as small molecule crystals took some time to be established, with the application of the newly developed tool of protein crystallography having a significant role. To better understand this transition and the more recent change in view regarding the continuum of relevant protein states including disordered proteins, it is worth considering the nature of scientific paradigms and their roles in guiding scientific progress (Kuhn, 1962Kuhn T.S. The Structure of Scientific Revolutions. The University of Chicago Press, Chicago1962Google Scholar). In this conception, scientific progress is seen not as a linear enhancement of knowledge but as a steady growth of understanding within certain defining and limiting theories or paradigms interrupted by dramatic changes in these paradigms to enable rapid development of knowledge. Thus, the paradigm of structure/function correlations, while facilitating significant biological insight, slowed the acceptance of the biological role of highly dynamic and disordered protein states. Dramatic shifts are often enabled by the application of new methods, with nuclear magnetic resonance (NMR) and computational approaches driving the more recent appreciation for the full dynamic continuum of relevant protein states. Regardless of these philosophical considerations, the increasing body of evidence for the presence and functional importance of dynamic and disordered protein states has now led to a general acknowledgment of the structural biological significance of characterizing these states. After all, if these proteins have biological functions, such functions must be enabled by their conformations and dynamics, and structural biology should be able to enlighten us with respect to their structure-dynamics-disorder/function relationships. Reviews of the history of the field of disordered proteins have been published with references to disorder from at least as far back as 1986 (Hernández et al., 1986Hernández M.A. Avila J. Andreu J.M. Physicochemical characterization of the heat-stable microtubule-associated protein MAP2.Eur. J. Biochem. 1986; 154: 41-48Crossref PubMed Google Scholar, Sigler, 1988Sigler P.B. Transcriptional activation. Acid blobs and negative noodles.Nature. 1988; 333: 210-212Crossref PubMed Google Scholar, Spolar and Record, 1994Spolar R.S. Record Jr., M.T. Coupling of local folding to site-specific binding of proteins to DNA.Science. 1994; 263: 777-784Crossref PubMed Google Scholar). Within the past 20 years, significant milestones include the description as intrinsically disordered proteins of p21, which is required for the biologically critical function of inhibition of cyclin-dependent kinases (Kriwacki et al., 1996Kriwacki R.W. Hengst L. Tennant L. Reed S.I. Wright P.E. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity.Proc. Natl. Acad. Sci. USA. 1996; 93: 11504-11509Crossref PubMed Google Scholar), and of alpha-synuclein, which is involved in synaptic activity and a fragment of which is found in Alzheimer's amyloid deposits (Weinreb et al., 1996Weinreb P.H. Zhen W. Poon A.W. Conway K.A. Lansbury Jr., P.T. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded.Biochemistry. 1996; 35: 13709-13715Crossref PubMed Scopus (842) Google Scholar). The observation that FlgM is required to be disordered for export but then folds upon binding to sigma factor (Daughdrill et al., 1997Daughdrill G.W. Chadsey M.S. Karlinsey J.E. Hughes K.T. Dahlquist F.W. The C-terminal half of the anti-sigma factor, FlgM, becomes structured when bound to its target, sigma 28.Nat. Struct. 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Based on these and many other important contributions over the past 20 years, a set of characteristics of intrinsically disordered proteins and regions (IDPs/IDRs) has been established that provide a context for functional correlations to augment those described for folded protein structures. (Note that for the remainder of the article, IDP will be used for both IDP and IDR.) These characteristics may be considered an interrelated set beginning with their sequence features and physical forces dominating their interactions through their structural, functional, and evolutionary properties (Figure 1). As has been exploited within computational algorithms for predicting protein disorder, IDPs are highly enriched in charged and polar residues, as well as glycine and proline, with fewer hydrophobic residues (Uversky et al., 2000Uversky V.N. Gillespie J.R. Fink A.L. 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Some IDPs can have high net charge, either positive or negative, with others having a mixture of charges with "blocks" or clusters of the same charge. These sequence features do not favor hydrophobic burial in the context of persistent secondary structural elements, precluding formation of folded protein structure. The few instances of large hydrophobic residues, such as tryptophan, tyrosine, phenylalanine, and leucine, found in IDPs are usually part of motifs that recognize binding partners (Fuxreiter et al., 2007Fuxreiter M. Tompa P. Simon I. Local structural disorder imparts plasticity on linear motifs.Bioinformatics. 2007; 23: 950-956Crossref PubMed Scopus (204) Google Scholar, Brown et al., 2010Brown C.J. Johnson A.K. Daughdrill G.W. Comparing models of evolution for ordered and disordered proteins.Mol. Biol. Evol. 2010; 27: 609-621Crossref PubMed Scopus (52) Google Scholar). IDPs also contain sequence motifs for recognition by enzymes carrying out posttranslational modification (PTM; Iakoucheva et al., 2004Iakoucheva L.M. Radivojac P. Brown C.J. O'Connor T.R. Sikes J.G. Obradovic Z. Dunker A.K. The importance of intrinsic disorder for protein phosphorylation.Nucleic Acids Res. 2004; 32: 1037-1049Crossref PubMed Scopus (559) Google Scholar). The accessibility of disordered chains facilitates both PTM and binding, leading to enrichment of PTM sites in IDPs and their preponderance as hub proteins, those having more than ten binding partners (Dunker et al., 2005Dunker A.K. Cortese M.S. Romero P. Iakoucheva L.M. Uversky V.N. Flexible nets. The roles of intrinsic disorder in protein interaction networks.FEBS J. 2005; 272: 5129-5148Crossref PubMed Scopus (511) Google Scholar, Higurashi et al., 2008Higurashi M. Ishida T. Kinoshita K. Identification of transient hub proteins and the possible structural basis for their multiple interactions.Protein Sci. 2008; 17: 72-78Crossref PubMed Scopus (41) Google Scholar). Obviously, the same physical forces apply to a disordered as to an ordered protein, but their relative importance in shaping structure and dynamics is different. The large degree of conformational sampling for IDPs gives them significant conformational entropy, which can be restricted by intra- and intermolecular interactions. It has been suggested that loss of conformational entropy upon binding results in significantly weaker binding for IDPs undergoing dramatic disorder-to-order transitions upon binding, facilitating high specificity but fast off-rates for regulatory interactions (Dunker et al., 1998Dunker A.K. Garner E. Guilliot S. Romero P. Albrecht K. Hart J. Obradovic Z. Kissinger C. Villafranca J.E. Protein disorder and the evolution of molecular recognition: theory, predictions and observations.Pac. 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The other forces, including van der Waals interactions and the hydrophobic effect, which are dominant for folded proteins, appear to be less important in general but specific cases of hydrophobic interactions and clustering in disordered proteins have been reported (Klein-Seetharaman et al., 2002Klein-Seetharaman J. Oikawa M. Grimshaw S.B. Wirmer J. Duchardt E. Ueda T. Imoto T. Smith L.J. Dobson C.M. Schwalbe H. Long-range interactions within a nonnative protein.Science. 2002; 295: 1719-1722Crossref PubMed Scopus (444) Google Scholar, Mittag et al., 2008Mittag T. Orlicky S. Choy W.Y. Tang X. Lin H. Sicheri F. Kay L.E. Tyers M. Forman-Kay J.D. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor.Proc. Natl. Acad. Sci. USA. 2008; 105: 17772-17777Crossref PubMed Scopus (122) Google Scholar, Meng et al., 2013Meng W. Lyle N. Luan B. Raleigh D.P. Pappu R.V. Experiments and simulations show how long-range contacts can form in expanded unfolded proteins with negligible secondary structure.Proc. Natl. Acad. Sci. USA. 2013; 110: 2123-2128Crossref PubMed Scopus (19) Google Scholar). Disordered protein energetics may be characterized by multiple weak interactions showing minimal cooperativity. The transient sampling of a large number of relatively weak intramolecular interactions within an IDP can enable the protein to act as its own solvent, leading to self-association as intramolecular contacts become indistinguishable from intermolecular contacts involving the same residues (Rauscher and Pomès, 2012Rauscher S. Pomès R. Aggregated yet disordered: a molecular simulation study of the self-aggregation of elastin.Biophys. J. 2012; 102: 40aAbstract Full Text Full Text PDF Google Scholar). The impact of these physical forces on IDPs leads to structural properties highly distinct from those of folded proteins. The dominant feature is lack of persistent secondary and tertiary structure, with a highly flexible chain transiently sampling fractional secondary structure and tertiary contacts (Daughdrill et al., 1998Daughdrill G.W. Hanely L.J. Dahlquist F.W. The C-terminal half of the anti-sigma factor FlgM contains a dynamic equilibrium solution structure favoring helical conformations.Biochemistry. 1998; 37: 1076-1082Crossref PubMed Scopus (75) Google Scholar, Choy and Forman-Kay, 2001Choy W.Y. Forman-Kay J.D. Calculation of ensembles of structures representing the unfolded state of an SH3 domain.J. Mol. Biol. 2001; 308: 1011-1032Crossref PubMed Scopus (134) Google Scholar, Dunker et al., 2001Dunker A.K. Lawson J.D. Brown C.J. Williams R.M. Romero P. Oh J.S. Oldfield C.J. Campen A.M. Ratliff C.M. Hipps K.W. et al.Intrinsically disordered protein.J. Mol. Graph. Model. 2001; 19: 26-59Crossref PubMed Scopus (962) Google Scholar). This flexibility enables motifs for PTM and binding to be accessible. Dynamic sampling of conformations can also facilitate averaging of electrostatic fields, leading to a dependence of structural (such as Rh) and binding properties on net charge or charge distributions (Borg et al., 2007Borg M. Mittag T. Pawson T. Tyers M. Forman-Kay J.D. Chan H.S. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity.Proc. Natl. Acad. Sci. USA. 2007; 104: 9650-9655Crossref PubMed Scopus (86) Google Scholar, Serber and Ferrell, 2007Serber Z. Ferrell Jr., J.E. Tuning bulk electrostatics to regulate protein function.Cell. 2007; 128: 441-444Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The fraction and linear patterning of charged residues significantly affects IDP conformations (Das and Pappu, 2013Das R. Pappu R.V. Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues.Proc. Natl. Acad. Sci. U S A. 2013; 110: 13392-13397Crossref PubMed Scopus (20) Google Scholar). PTMs can, in many cases, change the net charge and charge distribution (Seet et al., 2006Seet B.T. Dikic I. Zhou M.M. Pawson T. Reading protein modifications with interaction domains.Nat. Rev. Mol. Cell Biol. 2006; 7: 473-483Crossref PubMed Scopus (333) Google Scholar, Arif et al., 2010Arif M. Senapati P. Shandilya J. Kundu T.K. Protein lysine acetylation in cellular function and its role in cancer manifestation.Biochim. Biophys. Acta. 2010; 1799: 702-716Crossref PubMed Scopus (20) Google Scholar, Deribe et al., 2010Deribe Y.L. Pawson T. Dikic I. Post-translational modifications in signal integration.Nat. Struct. Mol. Biol. 2010; 17: 666-672Crossref PubMed Scopus (123) Google Scholar, Sasaki, 2012Sasaki N. 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Effect of phosphorylation on alpha-helix stability as a function of position.Biochemistry. 2002; 41: 1897-1905Crossref PubMed Scopus (67) Google Scholar). While the lack of persistent folded structure and fewer hydrophobic residues mean that there is no hydrophobic core, transient secondary structure and tertiary contacts, electrostatic interactions, and backbone torsion angle propensities, particularly for proline, translate into different degrees of compactness for IDPs. These range from quite compact and only slightly expanded relative to a folded domain to extended beyond that expected for a fully denatured domain of the same number of residues (Mao et al., 2013Mao A.H. Lyle N. Pappu R.V. Describing sequence-ensemble relationships for intrinsically disordered proteins.Biochem. J. 2013; 449: 307-318Crossref PubMed Scopus (18) Google Scholar). One way of understanding the structural properties of disordered proteins is viewing them as the "polymer" state of proteins, capable of occupying many different parts of the phase diagram of accessible protein states (Mao et al., 2010Mao A.H. Crick S.L. Vitalis A. Chicoine C.L. Pappu R.V. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins.Proc. Natl. Acad. Sci. USA. 2010; 107: 8183-8188Crossref PubMed Scopus (113) Google Scholar). Many IDPs are monomeric or participate in defined oligomers upon binding protein partners, either folded or disordered. IDPs can undergo disorder-to-order transitions upon binding, stabilizing isolated helical or extended regions or even a small ordered domain (Wright and Dyson, 2009Wright P.E. Dyson H.J. Linking folding and binding.Curr. Opin. Struct. 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Protein disorder, prion propensities, and self-organizing macromolecular collectives.Biochim. Biophys. Acta. 2013; 1834: 918-931Crossref PubMed Scopus (15) Google Scholar) or precede gelation or fiber formation (see below). Liquid droplet formation is arguably one of the most important new roles for IDPs identified in the last decade. While cases of folding upon binding result in a straightforward extension of the structure/function paradigm, the retention of significant disorder in dynamic complexes and liquid droplets underscores the functional relevance of the full continuum of protein states. Due to the dynamic nature of isolated IDPs and many of their complexes, standard biophysical tools are not easily applied for characterization of specific structural properties beyond polymer chain descriptors such as hydrodynamic radius (Rh), radius of gyration (Rg) and end-to-end distance distributions. 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