A Conserved Allosteric Pathway in Tyrosine Kinase Regulation

Marsiglia, William M.; Katigbak, Joseph; Zheng, Sijin; Mohammadi, Moosa; Zhang, Yingkai; Traaseth, Nathaniel J.

doi:10.1016/j.str.2019.05.002

Cited by 16 publications

(11 citation statements)

References 31 publications

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“…Indeed, both computational and experimental methods have successfully elucidated allosteric pathways in a variety of different systems outside of protein kinase A 45 – 52 . Perhaps more importantly, many of these studies have shown how disruptions in these pathways act to change function.…”

Section: Discussionmentioning

confidence: 99%

Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

et al. 2021

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An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-CDNAJB1) in which the J-domain of the heat shock protein 40 is fused to the catalytic α subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-CDNAJB1 has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera’s allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-CDNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.

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Section: Discussionmentioning

confidence: 99%

Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

et al. 2021

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“…Highly coupled motions between distant sites of KIT, as evidenced by the cross-correlation maps, suggests its association with the functional dependence of these regions, which is classified as allosteric regulation, the phenomenon largely observed in many proteins [2,3,53,54]. In particular, the coupling motions in each lobe, N-and C-lobe, of the TK domain and between the lobes reflect the allosteric regulation of the kinase function, which is well-described for different non-receptor and receptor tyrosine kinases [3,55,56]. The coupled motions of two activating regions of KIT, A-loop, and JMR were characterized, in terms of their allosteric communication in the wild-type KIT, which was disrupted in oncogenic mutants [40,57].…”

Section: Discussionmentioning

confidence: 75%

The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT

Ledoux

Trouvé

Tchertanov

2022

IJMS

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RTK KIT regulates a variety of crucial cellular processes via its cytoplasmic domain (CD), which is composed of the tyrosine kinase domain, crowned by the highly flexible domains—the juxtamembrane region, kinase insertion domain, and C-tail, which are key recruitment regions for downstream signalling proteins. To prepare a structural basis for the characterization of the interactions of KIT with its signalling proteins (KIT INTERACTOME), we generated the 3D model of the full-length CD attached to the transmembrane helix. This generic model of KIT in inactive state was studied by molecular dynamics simulation under conditions mimicking the natural environment of KIT. With the accurate atomistic description of the multidomain KIT dynamics, we explained its intrinsic (intra-domain) and extrinsic (inter-domain) disorder and represented the conformational assemble of KIT through free energy landscapes. Strongly coupled movements within each domain and between distant domains of KIT prove the functional interdependence of these regions, described as allosteric regulation, a phenomenon widely observed in many proteins. We suggested that KIT, in its inactive state, encodes all properties of the active protein and its post-transduction events.

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“…On the side of practical implications and from the perspective of the recently emerged paradigm of precision medicine, , allosteric ligands act as modulators ,, that induce noncompetitive and tunable allosteric regulation of protein activity, rendering them attractive in drug design. Specifically, allosteric drugs allow one to circumvent the side effects typical for orthosteric medicines aiming at the highly conserved orthosteric sites in two major drug targets, kinases and G protein-coupled receptors (GPCRs): (i) off-target toxicity caused by interactions with other kinases; ,− (ii) consequences of desensitization and internalization of GPCRs, ,,,, via binding to distal allosteric sites which are less conserved, thereby providing high selectivity and being less prone to inducing receptor desensitization/internalization compared to orthosteric drugs, respectively.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Allosteric Territory of Protein Function

et al. 2021

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While the pervasiveness of allostery in proteins is commonly accepted, we further show the generic nature of allosteric mechanisms by analyzing here transmembrane ion-channel viroporin 3a and RNA-dependent RNA polymerase (RdRp) from SARS-CoV-2 along with metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and fumarate hydratase (FH) implicated in cancers. Using the previously developed structure-based statistical mechanical model of allostery (SBSMMA), we share our experience in analyzing the allosteric signaling, predicting latent allosteric sites, inducing and tuning targeted allosteric response, and exploring the allosteric effects of mutations. This, yet incomplete list of phenomenology, forms a complex and unique allosteric territory of protein function, which should be thoroughly explored. We propose a generic computational framework, which not only allows one to obtain a comprehensive allosteric control over proteins but also provides an opportunity to approach the fragment-based design of allosteric effectors and drug candidates. The advantages of allosteric drugs over traditional orthosteric compounds, complemented by the emerging role of the allosteric effects of mutations in the expansion of the cancer mutational landscape and in the increased mutability of viral proteins, leave no choice besides further extensive studies of allosteric mechanisms and their biomedical implications.

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A Conserved Allosteric Pathway in Tyrosine Kinase Regulation

Cited by 16 publications

References 31 publications

Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT

Exploring the Allosteric Territory of Protein Function

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