The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases

Arbesú, Miguel; Maffei, Mariano; Cordeiro, Tiago N.; Teixeira, João M.C.; Pérez, Yolanda; Bernadó, Pau; Roche, Serge; Pons, Miquel

doi:10.1016/j.str.2017.02.011

Cited by 76 publications

(104 citation statements)

References 46 publications

(61 reference statements)

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“…Twelve of these, including the initial training set consisting of Histatin-5, ACTR and hNHE1, are sequences with lengths ranging from 24 to 273 that are unrelated in composition and biological functions. [46][47][48][49][50][51][52][53][54][55][56][57] The computed scattering profiles, I(q) as a function of the scattering vector q, bear close resemblance to those obtained from SAXS experiments, particularly in the low q regime, which describes the global structure of IDPs. The scattering profiles depicted in the Kratky representation (q 2 I(q)/I(0) vs q, Figs S1-S2) are also accurate at low q values.…”

Section: Sop-idp Model Accurately Reproduces Experimental Saxs Profilessupporting

confidence: 52%

Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

Baul

Chakraborty

Mugnai

et al. 2018

Preprint

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Intrinsically disordered proteins (IDPs) lack well-defined three-dimensional structures, thus challenging the archetypal notion of structure-function relationships. Determining the ensemble of conformations that IDPs explore under physiological conditions is the first step towards understanding their diverse cellular functions. Here, we quantitatively characterize the structural features of IDPs as a function of sequence and length using coarse-grained simulations. For diverse IDP sequences, with the number of residues (N T ) ranging from 24 to 441, our simulations not only reproduce the radii of gyration (R g ) obtained from experiments, but also predict the full scattering intensity profiles in very good agreement with Small Angle X-ray Scattering experiments.The R g values are well-described by the standard Flory scaling law,with ν ≈ 0.588, making it tempting to assert that IDPs behave as polymers in a good solvent. However, clustering analysis reveals that the menagerie of structures explored by IDPs is diverse, with the extent of heterogeneity being highly sequence-dependent, even though ensemble-averaged properties, such as the dependence of R g on chain length, may suggest synthetic polymer-like behavior in a good solvent. For example, we show that for the highly charged Prothymosin-α, a substantial fraction of conformations is highly compact. Even if the sequence compositions are similar, as is the case for α-Synuclein and a truncated construct from the Tau protein, there are substantial differences in the conformational heterogeneity. Taken together, these observations imply that metrics based on net charge or related quantities alone, cannot be used to anticipate the phases of IDPs, either in isolation or in complex with partner IDPs or RNA. Our work sets the stage for probing the interactions of IDPs with each other, with folded protein domains, or with partner RNAs, which are critical for describing the structures of stress granules and biomolecular condensates with important cellular functions.

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Section: Sop-idp Model Accurately Reproduces Experimental Saxs Profilessupporting

confidence: 52%

Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

Baul

Chakraborty

Mugnai

et al. 2018

Preprint

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“…Another example is given by the unique domain of Src-family kinases which contains an unusual number of hydrophobic residues for an IDR and which are intercalated with prolines. Arbesú et al [76] have shown that phenylalanine residues in this IDR promote the compaction of this protein, they hypothesize that proline residues may compensate the entropic cost of this effect by retaining correlated local flexibility, as proposed elsewhere [77]. Further evidence for the relevance of this sequence motif is provided by the fact that aromatic residues are found in pre-structured molecular recognition motifs (also called MoRFs and PreSMos [78]).…”

Section: Discussionmentioning

confidence: 77%

The Ambivalent Role of Proline Residues in an Intrinsically Disordered Protein: From Disorder Promoters to Compaction Facilitators

Mateos

Conrad-Billroth

Schiavina

et al. 2020

Journal of Molecular Biology

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Intrinsically disordered proteins (IDPs) carry out many biological functions. They lack a stable three-dimensional structure, but rather adopt many different conformations in dynamic equilibrium. The interplay between local dynamics and global rearrangements is key for their function. In IDPs, proline residues are significantly enriched. Given their unique physicochemical and structural properties, a more detailed understanding of their potential role in stabilizing partially folded states in IDPs is highly desirable. Nuclear magnetic resonance (NMR) spectroscopy, and in particular 13 C-detected NMR, is especially suitable to address these questions. We applied a 13 C-detected strategy to study Osteopontin, a largely disordered IDP with a central compact region. By employing the exquisite sensitivity and spectral resolution of these novel techniques we gained unprecedented insight into cis-Pro populations, their local structural dynamics and their role in mediating long-range contacts. Our findings clearly call for a reassessment of the structural and functional role of proline residues in IDPs. The emerging picture shows that proline residues have ambivalent structural roles. They are not simply disorder promoters but rather can, depending on the primary sequence context, act as nucleation sites for structural compaction in IDPs. These unexpected features provide a versatile mechanistic toolbox to enrich the conformational ensembles of IDPs with specific features for adapting to changing molecular and cellular environments.

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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 .…”

Section: Discussionmentioning

confidence: 99%

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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The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases

Cited by 76 publications

References 46 publications

Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

The Ambivalent Role of Proline Residues in an Intrinsically Disordered Protein: From Disorder Promoters to Compaction Facilitators

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

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