The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src

Maffei, Mariano; Arbesú, Miguel; Roux, Anabel‐Lise Le; Amata, Irene; Roche, Serge; Pons, Miquel

doi:10.1016/j.str.2015.03.009

Cited by 36 publications

(64 citation statements)

References 24 publications

(35 reference statements)

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“…Recent reports show that the region is also involved in interactions with the modular domains within the RM to possibly fine tune Src kinase activity 58 . These findings further highlight the functional similarity between Abl and Src kinases 59 . The quantitative dissection of the allosteric regulatory mechanism in Abl presented here revealed a hitherto unknown intramolecular activating region (cap PxxP ) in the cap.…”

Section: Discussionsupporting

confidence: 56%

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Saleh

Rossi

2017

Nat Struct Mol Biol

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The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We have used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) form synergistically a multilayered allosteric mechanism that enables Abl kinase to function as a finely-tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effect of various stimuli, activating or inhibiting, on the Abl kinase activity. The data provide the mechanistic basis for explaining genetic observations and reveal a novel activator region within Abl. Our findings show that drug-resistant mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

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Section: Discussionsupporting

confidence: 56%

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Saleh

Rossi

2017

Nat Struct Mol Biol

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“…The partner is either another SSB tetramer or, an interactome member. OB‐fold binding could potentially stabilize the intrinsically disordered linker, with the OB‐fold functioning as a scaffold, similar to what has been observed for the binding of the intrinsically disordered PXXP‐domain of the c‐Src protein to its SH3 partner 35,36 . In support of the linker/OB‐fold model, deletion or mutation of the linker or replacement of Escherichia coli SSB linkers with that from other bacterial species eliminates SSB function 3,37–39 .…”

Section: Introductionsupporting

confidence: 57%

The mechanism of Single strand binding protein–RecG binding: Implications for SSB interactome function

et al. 2020

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The Escherichia coli single-strand DNA binding protein (SSB) is essential to viability where it functions to regulate SSB interactome function. Here it binds to single-stranded DNA and to target proteins that comprise the interactome. The region of SSB that links these two essential protein functions is the intrinsically disordered linker. Key to linker function is the presence of three, conserved PXXP motifs that mediate binding to oligosaccharide-oligonucleotide binding folds (OB-fold) present in SSB and its interactome partners. Not surprisingly, partner OB-fold deletions eliminate SSB binding. Furthermore, single point mutations in either the PXXP motifs or, in the RecG OB-fold, obliterate SSB binding. The data also demonstrate that, and in contrast to the view currently held in the field, the C-terminal acidic tip of SSB is not required for interactome partner binding. Instead, we propose the tip has two roles.First, and consistent with the proposal of Dixon, to regulate the structure of the C-terminal domain in a biologically active conformation that prevents linkers from binding to SSB OB-folds until this interaction is required. Second, as a secondary binding domain. Finally, as OB-folds are present in SSB and many of its partners, we present the SSB interactome as the first family of OB-fold genome guardians identified in prokaryotes. K E Y W O R D SDNA helicase, OB-fold, PXXP motif, RecG, SH3 domain, single-strand binding protein, SSB interactome

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“…Such a property provides the possibility of achieving allosteric control in designed artificial nucleases . Similar allosteric regulation has recently been suggested, for example, the c‐Src kinase, based on the interdomain interactions restricting the conformational flexibility of the N‐terminal intrinsically disordered region or for the Pin1 peptidyl‐prolyl isomerase …”

Section: Discussionmentioning

confidence: 69%

Intrinsic protein disorder could be overlooked in cocrystallization conditions: An SRCD case study

et al. 2016

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X-ray diffractometry dominates protein studies, as it can provide 3D structures of these diverse macromolecules or their molecular complexes with interacting partners: substrates, inhibitors, and/or cofactors. Here, we show that under cocrystallization conditions the results could reflect induced protein folds instead of the (partially) disordered original structures. The analysis of synchrotron radiation circular dichroism spectra revealed that the Im7 immunity protein stabilizes the native-like solution structure of unfolded NColE7 nuclease mutants via complex formation. This is consistent with the fact that among the several available crystal structures with its inhibitor or substrate, all NColE7 structures are virtually the same. Our results draw attention to the possible structural consequence of protein modifications, which is often hidden by compensational effects of intermolecular interactions. The growing evidence on the importance of protein intrinsic disorder thus, demands more extensive complementary experiments in solution phase with the unligated form of the protein of interest.

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The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src

Cited by 36 publications

References 24 publications

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

The mechanism of Single strand binding protein–RecG binding: Implications for SSB interactome function

Intrinsic protein disorder could be overlooked in cocrystallization conditions: An SRCD case study

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