Nuclear magnetic resonance structure of an SH2 domain of phospholipase C-$gamma;1 complexed with a high affinity binding peptide

Pascal, Steven M.; Singer, Alex U.; Gish, G; Yamazaki, Toshio; Shoelson, Steven E.; Pawson, Tony; Kay, Lewis E.; Forman-Kay, Julie D.

doi:10.1016/0092-8674(94)90160-0

Cited by 250 publications

(206 citation statements)

References 55 publications

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“…In some cases, peptide studies may not provide accurate estimates of SH2 binding speci®city since synthetic peptides may not mimic all the structural features of SH2 binding sites on autophosphorylated receptors. In fact, this may be particularly true for PLCg and src family members where it has been shown that binding is not determined solely by the three amino acids carboxy-terminal to the phosphorylated tyrosine (Alonso et al, 1995;Songyang et al, 1995;Pascal et al, 1994;Larose et al, 1995). The optimal sequence carboxy-terminal to phosphotyrosine that binds to the src SH2 domain has been determined from a library of phosphopeptides and was found to be pYEEI.…”

Section: Discussionmentioning

confidence: 99%

“…This selectivity is consistent with the residues carboxy-terminal of Ufo Y821 (pYVNM). The PLCg domain speci®city also seems to include amino acids in position +4, +5 and +6, as well as residues N-terminal relative to phosphotyrosine (Pascal et al, 1994;Larose et al, 1993Larose et al, , 1995Eriksson et al, 1995). A comparison between the amino acid sequences surrounding the phosphorylated tyrosine residues involved in binding of PLCg to the Ufo receptor, and various other receptors, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

et al. 1997

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

et al. 1997

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“…Unlike the SH2N domain, the SH2C domain has three arginines in addition to the critical ␤5 arginine that may contribute to phosphotyrosine binding. There is also a long groove in which amino acids in the ϩ4, ϩ5, and ϩ6 positions, relative to the phosphotyrosine, may bind (20,24). These features may allow for a greater degree of variability in the binding capabilities of the SH2C domain than in those of the SH2N domain.…”

Section: Discussionmentioning

confidence: 99%

“…This represented Arg 586 in the SH2N domain and Arg 694 in the SH2C domain (6,33). The SH2C domain contains a second arginine (Arg 696 ), unique to the SH2C domain, that has previously been shown to have strong binding affinity for phosphorylated tyrosine 1021 in the PDGF receptor (24). Therefore, this arginine was also replaced with lysine to ensure complete disruption of the SH2C domain phosphotyrosine binding site ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These features may allow for a greater degree of variability in the binding capabilities of the SH2C domain than in those of the SH2N domain. Indeed, in order to ensure that we disabled the phosphotyrosine binding capacity of the SH2C domain, we used an SH2C mutant construct that contained a mutation in the ␤B5-arginine and the ␤B7-arginine that has been shown to have a strong association with a phosphotyrosine residue in the PDGF receptor (24). Our data indicate that the promiscuous binding potential is tightly regulated by the structure of PLC-␥1 and that alterations in the structure of PLC-␥1 that disrupt these normal control mechanisms can result in unregulated PLC-␥1 activity.…”

Section: Discussionmentioning

confidence: 99%

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Intramolecular Regulation of Phospholipase C-γ1 by Its C-Terminal Src Homology 2 Domain

DeBell

Graham

Reischl

et al. 2007

Molecular and Cellular Biology

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Phosphoinositide-specific phospholipase C-␥1 (PLC-␥1) is a key enzyme that governs cellular functions such as gene transcription, secretion, proliferation, motility, and development. Here, we show that PLC-␥1 is regulated via a novel autoinhibitory mechanism involving its carboxy-terminal Src homology (SH2C) domain. Mutation of the SH2C domain tyrosine binding site led to constitutive PLC-␥1 activation. The amino-terminal split pleckstrin homology (sPHN) domain was found to regulate the accessibility of the SH2C domain. PLC-␥1 constructs with mutations in tyrosine 509 and phenylalanine 510 in the sPHN domain no longer required an intact amino-terminal Src homology (SH2N) domain or phosphorylation of tyrosine 775 or 783 for activation. These data are consistent with a model in which the SH2C domain is blocked by an intramolecular interaction(s) that is released upon cellular activation by occupancy of the SH2N domain.Phosphoinositide-specific phospholipase C-␥1 (PLC-␥1) is activated in response to ligand binding by a variety of receptors (2). PLC-␥1 hydrolyzes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ], leading to the generation of the second messengers, inositol triphosphate (IP 3 ) and diacylglycerol, which release Ca 2ϩ from intracellular stores and activate Ras through the RasGRP/protein kinase C pathway, respectively (8, 13). PLC-␥1 has also been shown to play a role in the activation of NF-B (7). These pathways in turn initiate signaling cascades that culminate in cytokine production, activation of effector function, and cell proliferation (2, 5). The central role of PLC-␥1 in cellular function is further illustrated by the fact that inactivation of the PLC-␥1 gene in mice is embryonic lethal (16).Regulation of PLC-␥1 activity is complex. In quiescent cells, cytosolic sequestration of PLC-␥1 limits access to PI(4,5)P 2 in the plasma membrane. Cell stimulation induces membrane recruitment of PLC-␥1 and its tyrosine phosphorylation, essential steps in PLC-␥1 activation (2,23,36). Key components of PLC-␥ that are involved in these activation events are located within a region unique to PLC-␥ between the X and Y portions of the catalytic domain. This area is composed of two Src homology 2 (SH2) domains and an Src homology 3 (SH3) domain. The N-terminal SH2 domain (SH2N) is critical for binding to either tyrosine-phosphorylated receptor kinases or adaptor molecules that mediate PLC-␥1 relocation to the plasma membrane (6,14,25). The function of the C-terminal SH2 domain (SH2C) is less clear but is also essential for PLC-␥1 activation (1, 6, 14, 33). Interestingly, the tyrosine residues that are essential for PLC-␥1 activity (Y775 and Y783 in PLC-␥1 and Y753 and Y759 in PLC-␥2) are also located in this region (29,30).Components of the SH region not only are essential for PLC-␥1 activation but also may participate in its autoregulation. The individual X or Y elements of the catalytic domain alone are inactive. When mixed together in vitro, the hydrolytic activity of the combined X and Y elements was found...

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Src homology-2 domains: Structure, mechanisms, and drug discovery

Sawyer¹

1998

Biopolymers

129

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Src homology‐2 (SH2) domains and their associated catalytic or noncatalytic proteins constitute critical signal transduction targets for drug discovery. Such SH2 proteins are found in the regulation of a number of cellular processes, including growth, mitogenesis, motility, metabolism, immune response, and gene transcription. From the relationship of tyrosine phosphorylation and intracellular regulation by protein–tyrosine kinases (PTKs) and protein–tyrosine phosphatases (PTPs), the dynamic and reversible binding interactions of SH2 domain containing proteins with their cognate phosphotyrosine (pTyr) containing proteins provide a third dimensionality to the orchestration of signal transduction pathways that exist as a result of pTyr formation, degradation, and molecular recognition events. This review highlights several key research achievements impacting our current understanding of SH2 structure, mechanisms, and drug discovery that underlie the role(s) of SH2 domains in signal transduction processes, cellular functions, and disease states. © 1998 John Wiley & Sons, Inc. Biopoly 47: 243–261, 1998

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Nuclear magnetic resonance structure of an SH2 domain of phospholipase C-$gamma;1 complexed with a high affinity binding peptide

Cited by 250 publications

References 55 publications

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

Intramolecular Regulation of Phospholipase C-γ1 by Its C-Terminal Src Homology 2 Domain

Src homology-2 domains: Structure, mechanisms, and drug discovery

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