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  • Review Article
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Phosphotyrosine-binding domains in signal transduction

Nature Reviews Molecular Cell Biology volume 3, pages 177–186 (2002)Cite this article

Key Points

  • SH2 domains bind phosphotyrosine residues within the correct context of adjacent carboxy-terminal amino acids.

  • SH2 domains contain a 7-stranded b-meander, and bind with their peptide ligands that lie perpendicular to the central b-sheet.

  • SH2 domains couple receptor tyrosine kinases to downstream signalling pathways and participate in the regulation of cytosolic tyrosine kinases and phosphatases.

  • PTB domains, like SH2 domains, also bind to phosphotyrosine-containing sequence motifs within the correct context of the adjacent amino-terminal amino acids.

  • Some PTB domains bind to their ligands in a phospho-independent manner.

  • PTB domains consist of a 7-stranded b-sandwich with the bound peptide ligand often forming an extra anti-parallel b-strand.

  • PTB-domain-containing proteins commonly function as scaffolds and adaptor proteins downstream from membrane-bound receptors.

  • Molecular defects in SH2 and PTB domains that impair ligand binding are associated with human disease.

Abstract

Protein phosphorylation provides molecular control of complex physiological events within cells. In many cases, phosphorylation on specific amino acids directly controls the assembly of multi-protein complexes by recruiting phospho-specific binding modules. Here, the function, structure, and cell biology of phosphotyrosine-binding domains is discussed.

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Figure 1: Modular architecture of some SH2-domain-containing proteins.
Figure 2: Schematic of the PDGF receptor.
Figure 3: Molecular mechanism of SH2-domain function.
Figure 4: Modular architecture of PTB-domain-containing proteins.
Figure 5: Ribbons representation of the SHC PTB domain.
Figure 6: Comparison of the structures of SH2 and PTB phosphotyrosine-binding domains.

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Acknowledgements

I apologize to the many investigators whose work was not mentioned due to space constraints. This review benefited from helpful discussions with B. Neel and A. Kazlauskas. I am grateful to T. Pawson and B. Margolis for suggestions and critical reading of the manuscript and to L. Cantley for continued advice, support and encouragement. Financial support from NIH grants and a Career Development Award from the Burroughs-Wellcome Fund are gratefully acknowledged.

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  1. Department of Biology, Center for Cancer Research, E18-580, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139-4307, MA, USA

    Michael B. Yaffe

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DATABASES

Interpro:

C2

CH

ITAMs

PDZ

PH

PIDs

PLCXc

PLCYc

PTPase

RasGAP

RBD

RGS

SH2

SH3

WW

 LocusLink:

Nck

 Swiss-Prot:

ApoER2

c-Cbl

Disabled

EGF receptor

ErbB2

FE65

Gab1

Gab2

Grb2

Grb10

IRS-1

JIP-1

Lck

Lnx

LDLR

LET-23

Met

Nak

Numb

p85 subunit of PI3K

PDGFβ receptor

PLCγ

RasGAP

Reelin

SAP

SHC

SHP-1

SHP-2

SOS

Syk

Tek/Tie2

TrkA

VASP

VLDLR

X11

ZAP-70

Glossary

PROTEOME

The entire protein complement of an organism.

MESANGIAL CELL

A type of kidney cell that contacts endothelial cells in glomerular capillaries.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of ∼100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidyl-inositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

RING-FINGER PROTEINS

A family of proteins that are structurally defined by the presence of a zinc-binding RING-finger motif. The RING consensus sequence is: CX2CX(9–39)CX(1–3)HX(2–3)C/HX2CX(4–48)CX2C. The cysteines and histidines represent metal-binding sites. The first, second, fifth and sixth of these bind one zinc ion and the third, fourth, seventh and eighth bind the second.

ALLOSTERIC ACTIVATOR

A protein or enzyme that binds to its substrate, modulates the shape of it and positively influences its activity.

E2 ENZYME

An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 enzyme and transfers it to the substrate, mostly by using an E3 enzyme.

TYPE II POLYPROLINE HELIX

A structure that serves as a docking site for the Src-homology-3 domain.

β-SANDWICH

A tertiary protein structure that is common to all immuno-globulins. Consists of β-strands arranged into two β-sheets that pack together as a sandwich.

ENTHALPY

The thermodynamic property of a system, which includes changes in internal energy and work done on the surroundings.

ENTROPY

A thermodynamic property related to the state of disorder of a system.

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Yaffe, M. Phosphotyrosine-binding domains in signal transduction. Nat Rev Mol Cell Biol 3, 177–186 (2002). https://doi.org/10.1038/nrm759

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