Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form

Sigalov, Alexander B.; Zhuravleva, Anastasia; Orekhov, Vladislav Yu.

doi:10.1016/j.biochi.2006.11.003

Cited by 123 publications

(146 citation statements)

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“…These results suggest that the monomeric forms of UmuD and UmuDЈ, if they are ever present in solution, would be disordered and may undergo some disorder-to-order transition upon homodimerization (44). However, recent data show that a disorder-to-order transition is not necessary for homodimerization of one IDP, the T cell receptor -subunit (46). UmuD 2 and UmuDЈ 2 share homology with the dimerization domains of certain bacterial transcription factors (47).…”

Section: Discussionmentioning

confidence: 97%

Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products

Simon

Sousa²,

Mohana‐Borges³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Products of the umuD gene in Escherichia coli play key roles in coordinating the switch from accurate DNA repair to mutagenic translesion DNA synthesis (TLS) during the SOS response to DNA damage. Homodimeric UmuD 2 is up-regulated 10-fold immediately after damage, after which slow autocleavage removes the Nterminal 24 amino acids of each UmuD. The remaining fragment, UmuD 2, is required for mutagenic TLS. The small proteins UmuD2 and UmuD 2 make a large number of specific protein-protein contacts, including three of the five known E. coli DNA polymerases, parts of the replication machinery, and RecA recombinase. We show that, despite forming stable homodimers, UmuD 2 and UmuD 2 have circular dichroism (CD) spectra with almost no ␣-helix or ␤-sheet signal at physiological concentrations in vitro. High protein concentrations, osmolytic crowding agents, and specific interactions with a partner protein can produce CD spectra that resemble the expected ␤-sheet signature. A lack of secondary structure in vitro is characteristic of intrinsically disordered proteins (IDPs), many of which act as regulators. A stable homodimer that lacks significant secondary structure is unusual but not unprecedented. Furthermore, previous single-cysteine cross-linking studies of UmuD 2 and UmuD 2 show that they have a nonrandom structure at physiologically relevant concentrations in vitro. Our results offer insights into structural characteristics of relatively poorly understood IDPs and provide a model for how the umuD gene products can regulate diverse aspects of the bacterial SOS response.natively unfolded ͉ SOS response ͉ unstructured ͉ denatured ͉ DNA repair

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Section: Discussionmentioning

confidence: 97%

Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products

Simon

Sousa²,

Mohana‐Borges³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Anhydrin must bind DNA to effect its function, and NMR and slot-blot experiments confirm this, but CD and FTIR spectroscopy show that the protein does not thereby gain recognized secondary structure. This does not exclude the adoption of a specific spatial orientation with respect to its substrate but means that the polypeptide chain must remain extended in contact with DNA; a few other cases of IDPs remaining entirely disordered in the bound state are known (35,36). A nuclease function for anhydrin would be of value in anhydrobiosis where desiccation is expected to cause DNA breakage, tangling, and stalled replication forks, resulting in structures that require resolution, repair, or removal during the rehydration phase.…”

Section: Discussionmentioning

confidence: 99%

Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance

Chakrabortee

Meersman

Schierle

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) lack well-defined structure but are widely represented in eukaryotic proteomes. Although the functions of most IDPs are not understood, some have been shown to have molecular recognition and/or regulatory roles where their disordered nature might be advantageous. Anhydrin is an uncharacterized IDP induced by dehydration in an anhydrobiotic nematode, Aphelenchus avenae. We show here that anhydrin is a moonlighting protein with two novel, independent functions relating to desiccation tolerance. First, it has a chaperone-like activity that can reduce desiccation-induced enzyme aggregation and inactivation in vitro. When expressed in a human cell line, anhydrin localizes to the nucleus and reduces the propensity of a polyalanine expansion protein associated with oculopharyngeal muscular dystrophy to form aggregates. This in vivo activity is distinguished by a loose association of anhydrin with its client protein, consistent with a role as a molecular shield. In addition, anhydrin exhibits a second function as an endonuclease whose substrates include supercoiled, linear, and chromatin linker DNA. This nuclease activity could be involved in either repair of desiccation-induced DNA damage incurred during anhydrobiosis or in apoptotic or necrotic processes, for example, but it is particularly unexpected for anhydrin because IDP functions defined to date anticorrelate with enzyme activity. Enzymes usually require precise three-dimensional positioning of residues at the active site, but our results suggest this need not be the case. Anhydrin therefore extends the range of IDP functional categories to include catalysis and highlights the potential for the discovery of new functions in disordered proteomes.anhydrobiosis | endonuclease | intrinsically unstructured protein | molecular shield | natively unfolded protein

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“…Although an interaction of an IDP/IDPR with its binding partner is often accompanied by a disorder-to-order transition resulting in a (partial) folding of an IDP (9, 38, 50, 53, 54, 56 -59), many IDPs/IDPRs form fuzzy complexes in which they remain predominantly disordered, at least outside the binding interface (61)(62)(63)(64)(65)(66)(67)(68). Similar to the disordered regions of unbound IDPs, these under-folded, fuzzy regions of bound IDPs/IDPRs have multiple functions, e.g.…”

Section: Binding-induced Under-folding: Fuzziness Of Disorder-based Cmentioning

confidence: 99%

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

Uversky

2016

Journal of Biological Chemistry

190

182

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Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs.Brief Introduction: Why Those Proteins Are Clouds and Why Those Clouds Are Dancing "Dancing protein clouds" is a joke from a time when the newly born field of protein intrinsic disorder was trying to find an appropriate term to describe biologically active proteins without unique structures. The need for a specific term was determined by the clear recognition that those structureless functional proteins were fundamentally different from the "normal" globular proteins that used information encoded in their amino acid sequences to fold into specific, aperiodic crystal-like structures needed for specific biological functions. Fig. 1 reflects these attempts by representing different terms used in literature to describe such "strange" or "abnormal" proteins and shows that the "dancing protein clouds" expression is formed by superimposing "dancing proteins" and "protein clouds" descriptors. Although the phrase "dancing protein clouds" sounds like a parody, the term actually has deep meanings. The presence of a unique structure in a given protein means that when one would look at the sample containing this protein, s/he would find that all protein molecules are alike, that the structure of an individual molecule barely changes over time, and that the ensemble-averaged (or time-averaged) structure is identical, or at least very similar, to the structures of all individual protein molecules in that sample. In other words, if one would overlay all those individual structures, a crisp and clear image would be generated, similar to those found in the Protein Data Bank (PDB), and this ensemble-averaged structure would not change much over time. On the other hand, the lack of a unique structure in a given protein would create a highly dynamic ensemble, members of which would possess very different structures at any given moment, and the structure of any given molecule would change dramatically over time (therefore the "dancing protein" analogy). If one would try to overlay all those structures,...

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Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form

Cited by 123 publications

References 13 publications

Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products

Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products

Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

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