Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners

Oldfield, Christopher J.; Meng, Jingwei; Yang, Jack; Yang, Mary Qu; Uversky, Vladimir N.; Dunker, A. Keith

doi:10.1186/1471-2164-9-s1-s1

Cited by 527 publications

(555 citation statements)

References 150 publications

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“…Furthermore, the acetate groups both became buried in the interfaces between the two MoRFs and their respective partners. 48 In this study, we discovered that differences in PTMs occur commonly when MoRFs bind to alternative partners. Furthermore, this use of modified side chains to bind to one of two partners is most common when the two partners are structurally distinct.…”

Section: Discussionmentioning

confidence: 94%

“…Using sequence characteristics that indicate short binding regions within longer regions of disorder offers a second strategy that does not depend on specific motifs, and several predictors have been developed that use this second strategy. [46][47][48][49][50] Such predictors have been used by experimentalists to help with the identification of binding regions within longer regions of disorder. 39,51 Both a hub protein's ability to bind multiple partners and the general importance of PPIs suggest that the use of flexibility for partner binding by IDPs and IDP regions is of considerable interest.…”

Section: Introductionmentioning

confidence: 99%

“…For the latter, we know of only two atomic resolution comparisons of more than one IDP binding to a single partner: namely, two different peptides binding to the TAZ1 domain, 30 and five different peptides binding to 14-3-3f. 48 With regard to the former, we likewise know of just three published examples: namely, a short segment from HIF1a bound to two partners, the TAZ1 domain and the asparagine hydroxylase FIH protein, 30 a short segment from the C-terminus of p53 bound to four partners, S100bb, sirtuin, CREB binding protein, and cyclin A2, 48 and a larger collection of various short segments bound to multiple partners. 52 We have carried out data mining on the Protein Data Bank (PDB) to find additional examples of both one-to-many and many-to-one complexes at atomic resolution.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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“…40,41 Here, B70% of the interactions of p53 are mediated by IDPRs containing 86, 90, and 100% of observed acetylation, phosphorylation, and protein conjugation sites of this protein, respectfully. 42 Early on, X-ray and NMR structural analysis revealed that an important inhibitor of PCD, BCL-x L , contains a 60-residue IDPR connecting helices al and a2. 43 Other members of the BCL-2 family, BH3-only proteins (such as BIM, BAD, and BMF) that serve as key initiators of PCD are largely disordered in solution.…”

Section: Discussionmentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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“…Disorder also allows some very unusual interactions; the yeast ubiquitin ligase San1, for example, recognizes misfolded substrates [159] and the CDK inhibitor Sic1 interacts with a single site on Cdc4 via multiple dispersed phosphorylation sites [158]. The hub proteins already mentioned frequently contain disordered regions [160] that are used to interact with a variety of partners [93].…”

Section: Disordered Proteins and Protein Segments Are Crucial For Celmentioning

confidence: 99%

Beyond ‘furballs’ and ‘dumpling soups’ – towards a molecular architecture of signaling complexes and networks

2012

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a b s t r a c tThe molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing.

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Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners

Cited by 527 publications

References 150 publications

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Beyond ‘furballs’ and ‘dumpling soups’ – towards a molecular architecture of signaling complexes and networks

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