Inter-cellular communication in multi-cellular animals relies on the specific
formation of protein-protein interactions in response to the activation of cell
surface receptors by hormones, cytokines and other protein messengers. One of
the most important mechanisms for the formation of such protein-protein interactions
involves the recognition of specific phosphorylated tyrosine residues by small
modular units of protein structure known as SH2 (Src-homology domain 2) domains.
This paper presents the first crystal structure of an SH2 domain (that of the
Src tyrosine kinase), complexed to a peptide containing a phosphorylated tyrosine
residue (two other groups, led by David Cowburn and Ian Campbell, reported NMR
structures for unliganded SH2 domains simultaneous with the publication of this
paper). Waksman et al. established the principles governing the recognition
of phosphorylated tyrosines by SH2 domains. The recognition of peptide segments
by targeting modules is now known to be an important and very extensive feature
of eukaryotic signaling, and the Waksman et al. paper presents the first example
of the structure for such a targeting interaction.
The determination of the first SH2-peptide structure proceeded particularly
rapidly because of an extensive collaborative network that developed from an
intense desire to solve this structure. Our lab, collaborating with Saburo Hanafusa's
group at Rockefeller, started an attack on the Src protein, in which we were
greatly assisted by further insights into Src provided by Marilyn Resh (Sloan-Kettering
Institute) and colleagues. At the same time, David Cowburn's group at Rockefeller,
working with David Baltimore and colleagues, determined a preliminary secondary
structure map for the SH2 domain of the Abl tyrosine kinase, using solution
NMR methods. This secondary structure enabled the crystal structure of the Src
SH2 domain to be determined extremely rapidly, by maximizing the utility of
poorly phased electron density maps. Nalin Pant, in David Cowburn's group, provided
the crucial peptides at a time when tyrosine phosphorylated peptides of high
purity were hard to come by.
Structures are available for two different low affinity peptides bound to the SH2 domain of v-Src (below). The structure of a high affinity peptide complex was determined in a later study.
Protein Structure Coordinates: 1SHA, 1SHB
Structure of the SH2-peptide complex
Phosphotyrosine
recognition. Left, electron density at 1.5 Angstroms. Right, van der Waals surfaces.
