Abstract
Phosphotyrosine (pY) signaling is instrumental to numerous cellular processes. pY recognition occurs through specialized protein modules, among which the Src-homology 2 (SH2) domain is the most common. SH2 domains are small protein modules with an invariant fold, and are present in more than a hundred proteins with different function. Here we ask the question of how such a structurally conserved, small protein domain can recognize distinct phosphopeptides with the breath of binding affinity, specificity and kinetic parameters necessary for proper control of pY-dependent signaling and rapid cellular response. We review the current knowledge on structure, thermodynamics and kinetics of SH2–phosphopeptide complexes and conclude that selective phosphopeptide recognition is governed by both structure and dynamics of the SH2 domain, as well as by the kinetics of the binding events. Further studies on the thermodynamic and kinetic properties of SH2–phosphopeptide complexes, beyond their structure, are required to understand signaling regulation.
Highlights
Eukaryotic cells use phosphorylation of tyrosine residues as one of the major routes of regulation of vital processes such as growth, survival, cytoskeletal reorganization, adhesion, metabolic homeostasis, and others (Hunter, 2009)
We review the current knowledge on structure, thermodynamics and kinetics of Src-homology 2 (SH2)–phosphopeptide complexes and conclude that selective phosphopeptide recognition is governed by both structure and dynamics of the SH2 domain, as well as by the kinetics of the binding events
The complexity of phosphotyrosine-dependent signaling is impressive, especially since most of the pY recognizing domains belong to the family of SH2 domains with a well-conserved fold and pY recognition mode
Summary
Eukaryotic cells use phosphorylation of tyrosine residues as one of the major routes of regulation of vital processes such as growth, survival, cytoskeletal reorganization, adhesion, metabolic homeostasis, and others (Hunter, 2009). PY signaling requires the presence of protein domains capable of binding to amino acid sequences containing this residue. A prominent example is the protein adapter Grb in the context of Ras/MAPK signaling, whose SH2 domain recognizes tyrosyl-phosphorylated sequences of the cytosolic domain of receptor tyrosine kinases (RTKs): this allows the localization of the guanine-nucleotide exchange factor SOS, which is bound to Grb, in the proximity of Ras, leading to its activation (Lemmon and Schlessinger, 2010). The question of how a relatively invariant fold such as the SH2 domain achieves the specificity and binding kinetics required for proper control of pY-dependent signaling has been the subject of intense investigation. We conclude that a full understanding of binding specificity and regulation of enzyme activity through pY-dependent signaling requires consideration of both structure and dynamics of the molecules involved, as well as non-equilibrium kinetic processes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
