Structure and ligand recognition of the phosphotyrosine binding domain of Shc

Zhou, Ming‐Ming; Ravichandran, Kodi S.; Olejniczak, Edward T.; Petros, Andrew M.; Meadows, Robert P.; Sattler, Michael; Harlan, John E.; Wade, Warren S.; Burakoff, Steven J.; Fesik, Stephen W.

doi:10.1038/378584a0

Cited by 353 publications

(413 citation statements)

References 49 publications

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“…Both of these PTB domains recognize phosphopeptides in which amino acids N-terminal to the pTyr bind as a supplementary b-strand to an antiparallel b-sheet of the PTB module; the NPXpY motif then forms a bturn, positioning the phosphorylated Tyr for interaction with solvent exposed basic residues. In the Shc and IRS-1 PTB domains di erent residues recognize the bound pTyr, suggesting that these individual PTB domains might have independently acquired an ability to recognize phosphorylated Tyr (Eck et al, 1996;Zhou et al, 1995). Consistent with this view, PTB domains from proteins such as X11, Fe65 and Numb can bind tightly to non-phosphorylated peptides (Borg et al, 1996;Fiore et al, 1995;Li et al, 1997), suggesting that PTB domains may have originally developed as modules that recognize peptides with bturn structures, independently of phosphorylation.…”

Section: Introductionmentioning

confidence: 75%

“…These PTB domains are functionally similar to SH2 domains in the sense that they bind directly to short peptide motifs in a fashion that is regulated by phosphorylation of the ligand, and depends on residues¯anking the phosphorylation site (Songyang et al, 1995). However, the structures of the Shc and IRS-1 PTB domains, and the mechanisms by which they recognize speci®c phosphopeptides, are quite di erent from those displayed by SH2 domains (Eck et al, 1996;Zhou et al, 1995). SH2 domains possess a conserved pTyrbinding pocket, with an invariant buried Arg that coordinates the phosphate oxygens.…”

Section: Introductionmentioning

confidence: 99%

“…In general, the phosphopeptide ligand lies orthogonally to a central anti-parallel b-sheet on the SH2 domain, such that peptide residues C-terminal to the pTyr contact a variable binding surface, and thereby determine the speci®city of SH2 domain-phosphopeptide interactions (Kuriyan and Cowburn, 1997). The Shc and IRS-1 PTB domains are structurally closely related to one another, and possess a similar fold to PH domains, but are entirely distinct from SH2 domains (Eck et al, 1996;Kuriyan and Cowburn, 1997;Zhou et al, 1995). Both of these PTB domains recognize phosphopeptides in which amino acids N-terminal to the pTyr bind as a supplementary b-strand to an antiparallel b-sheet of the PTB module; the NPXpY motif then forms a bturn, positioning the phosphorylated Tyr for interaction with solvent exposed basic residues.…”

Section: Introductionmentioning

confidence: 99%

“…The Shc PTB domain requires a large aliphatic amino acid at the 75 position (®ve residues N-terminal to the pTyr), which occupies a hydrophobic pocket on the PTB domain (van der Geer et al, 1996a;Zhou et al, 1995), whereas the IRS-1 PTB domain binds preferentially to phosphopeptide ligands with hydrophobic residues at the 76 to 78 positions (He et al, 1995). Presumably as a consequence of this distinction in binding properties, Shc and IRS-1 show di erent interactions with receptor protein-tyrosine kinases.…”

Section: Introductionmentioning

confidence: 99%

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Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

1999

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Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess phosphotyrosine-binding (PTB) domains, through which they bind speci®c activated receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1 creates binding sites for the SH2 domains of multiple signaling proteins, leading to the activation of intracellular biochemical pathways. The PTB domains of Shc and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has suggested that residues N-terminal to the NPXpY motif may determine the a nity with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor (IR) b subunit in vitro, owing to its low a nity for the NPXpY autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not bind stably to the activated IR in cells. We show that substitution of Ser 955, ®ve residues Nterminal to the Tyr 960 autophosphorylation site (the 75 position), with Ile alters the target speci®city of the IR such that it stably associates with Shc in insulinstimulated cells. A triple substitution of the 75, 78 and 79 residues relative to Tyr 960 of the IR to the corresponding amino acids found in the Shc PTB domain binding site of TrkA results in even stronger binding of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc showed an increased ability to activate the MAPK pathway in response to insulin stimulation. These results demonstrate that subtle di erences in residues N-terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind speci®c PTB domain proteins in vivo, and thus modify the signaling properties of activated receptors.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

1999

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“…Hence, prediction of new PH‐like domains may identify residues that are functionally important for intracellular traffic. Since the initial discovery of classical PH domains, newly solved PH‐like structures have unexpectedly been found, both early on,17 and at least 10 times since 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. Each of these discoveries added a new family of PH‐like domains to a growing PH‐like clan 28.…”

Section: Introductionmentioning

confidence: 99%

Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains

Fidler¹,

Murphy²,

Courtis³

et al. 2016

Traffic

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Advances in membrane cell biology are hampered by the relatively high proportion of proteins with no known function. Such proteins are largely or entirely devoid of structurally significant domain annotations. Structural bioinformaticians have developed profile‐profile tools such as HHsearch (online version called HHpred), which can detect remote homologies that are missed by tools used to annotate databases. Here we have applied HHsearch to study a single structural fold in a single model organism as proof of principle. In the entire clan of protein domains sharing the pleckstrin homology domain fold in yeast, systematic application of HHsearch accurately identified known PH‐like domains. It also predicted 16 new domains in 13 yeast proteins many of which are implicated in intracellular traffic. One of these was Vps13p, where we confirmed the functional importance of the predicted PH‐like domain. Even though such predictions require considerable work to be corroborated, they are useful first steps. HHsearch should be applied more widely, particularly across entire proteomes of model organisms, to significantly improve database annotations.

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A phosphoinositide-binding sequence is shared by PH domain target molecules—a model for the binding of PH domains to proteins

Alberti

1998

Proteins

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Pleckstrin homology (PH) domains have been proven to bind phosphoinositides (PI) and inositolphosphates (IP). On the other hand, a binding of PH domains to proteins is still a matter of debate. The goal of this work was to identify potential PH domain protein target sites and to build a model for PH domain-protein binding. A candidate sequence, called HIKE, was identified by sequence homology analysis of the proteins that are considered the strongest PH binding candidates, i.e., Gbeta, PKC, and Akt. HIKE contains a PI binding sequence and fulfills several criteria for a potential PH-binding site, i.e., it is present in other PH-binding candidates, lies in regulatory regions independently predicted to bind PH domains, and is conserved in 3-D structure among different molecules. These findings and the similarities with the mode of binding of PTB and PDZ domains suggest a beta strand-beta strand coordination model for PH-protein binding. The HIKE model predicts that membrane anchoring of PH domains and their targets could be a critical step in their interaction, which would consistently explain why PH-protein binding has only been detected in the presence of PI.

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Structure and ligand recognition of the phosphotyrosine binding domain of Shc

Cited by 353 publications

References 49 publications

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains

A phosphoinositide-binding sequence is shared by PH domain target molecules—a model for the binding of PH domains to proteins

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