Intramolecular Dynamics within the N-Cap-SH3-SH2 Regulatory Unit of the c-Abl Tyrosine Kinase Reveal Targeting to the Cellular Membrane

Oliveira, Guilherme A. P. de; Pereira, Elen Gomes; Ferretti, Giulia D. S.; Valente, Ana Paula; Cordeiro, Yraima; Silva, Jerson L.

doi:10.1074/jbc.m113.500926

Cited by 15 publications

(20 citation statements)

References 38 publications

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“…1a): an unstructured N-terminal region referred to as the cap (residues 1–80), the SH3 domain (residues 85–138), a short linker referred to as the connector SH3/2 (residues 139–152) that connects the SH3 to the SH2 domain (residues 153–237), and a linker (linker SH2-KD ; residues 238–250) that connects the SH2 to KD (residues 255–534) 8 . To delineate the conformational landscape of Abl RM, we used NMR 27,28 to determine the intrinsic structural and dynamic properties of the isolated Abl RM (residues 1–255) (Supplementary Fig. 1a,b).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…One possibility is that PxxPxR motifs could facilitate structural stability in the SH3 domain-containing proteins. In support of this idea, recent studies have shown that the linker regions surrounding SH3 and other interaction domains in Abl and PLC-γ1 regulate the dynamics of the interaction cassettes [39–41]. The PxxPxR motifs could be critical for the stable binding with SH3 domains.…”

Section: Discussionmentioning

confidence: 99%

Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands

Bartelt

Light

Vacaflores

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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SH3 domains are evolutionarily conserved protein interaction domains that control nearly all cellular processes in eukaryotes. The current model is that most SH3 domains bind discreet PxxPxR motifs with weak affinity and relatively low selectivity. However, the interactions of full-length SH3 domain-containing proteins with ligands are highly specific and have much stronger affinity. This suggests that regions outside of PxxPxR motifs drive these interactions. In this study, we observed that PxxPxR motifs were required for the binding of the adaptor protein GRB2 to short peptides from its ligand SOS1. Surprisingly, PxxPxR motifs from the proline rich region of SOS1 or CBL were neither necessary nor sufficient for the in vitro or in vivo interaction with full-length GRB2. Together, our findings show that regions outside of the consensus PxxPxR sites drive the high affinity association of GRB2 with SH3 domain ligands, suggesting that the binding mechanism for this and other SH3 domain interactions may be more complex than originally thought.

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“…Src family member abl also binds membranes through its SH4 and SH3 domains, and abl translocation changes the downstream events induced by the kinase (de Oliveira et al, 2013). The bcr-abl hybrid associated with leukemia shows lower membrane association than the nononcogenic form and alteration of tyrosine kinase-membrane binding may be a future line of cancer therapy.…”

Section: Activation Of Src By Pa Pi4p Uroplakin Pld G Proteins Cmentioning

confidence: 99%

Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

Stith

2015

Developmental Biology

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This review emphasizes how lipids regulate membrane fusion and the proteins involved in three developmental stages: oocyte maturation to the fertilizable egg, fertilization and during first cleavage. Decades of work show that phosphatidic acid (PA) releases intracellular calcium, and recent work shows that the lipid can activate Src tyrosine kinase or phospholipase C during Xenopus fertilization. Numerous reports are summarized to show three levels of increase in lipid second messengers inositol 1,4,5-trisphosphate and sn 1,2-diacylglycerol (DAG) during the three different developmental stages. In addition, possible roles for PA, ceramide, lysophosphatidylcholine, plasmalogens, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 4,5-bisphosphate, membrane microdomains (rafts) and phosphatidylinositol 3,4,5-trisphosphate in regulation of membrane fusion (acrosome reaction, sperm-egg fusion, cortical granule exocytosis), inositol 1,4,5-trisphosphate receptors, and calcium release are discussed. The role of six lipases involved in generating putative lipid second messengers during fertilization is also discussed: phospholipase D, autotaxin, lipin1, sphingomyelinase, phospholipase C, and phospholipase A2. More specifically, proteins involved in developmental events and their regulation through lipid binding to SH3, SH4, PH, PX, or C2 protein domains is emphasized. New models are presented for PA activation of Src (through SH3, SH4 and a unique domain), that this may be why the SH2 domain of PLCγ is not required for Xenopus fertilization, PA activation of phospholipase C, a role for PA during the calcium wave after fertilization, and that calcium/calmodulin may be responsible for the loss of Src from rafts after fertilization. Also discussed is that the large DAG increase during fertilization derives from phospholipase D production of PA and lipin dephosphorylation to DAG.

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Intramolecular Dynamics within the N-Cap-SH3-SH2 Regulatory Unit of the c-Abl Tyrosine Kinase Reveal Targeting to the Cellular Membrane

Cited by 15 publications

References 38 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

Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands

Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

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