title: Energetics of Src homology domain interactions in receptor tyrosine kinase-mediated signaling.
abstract: Intracellular signaling from receptor tyrosine kinases (RTK) on extracellular stimulation is fundamental to all cellular processes. The protein-protein interactions which form the basis of this signaling are mediated through a limited number of polypeptide domains. For signal transduction without corruption, based on a model where signaling pathways are considered as linear bimolecular relays, these interactions have to be highly specific. This is particularly the case when one considers that any cell may have copies of similar binding domains found in numerous proteins. In this work, an overview of the thermodynamics of binding of two of the most common of these domains (SH2 and SH3 domains) is given. This, coupled with insight from high-resolution structural detail, provides a comprehensive survey of how recognition of cognate binding sites for these domains occurs. Based on the data presented, we conclude that specificity offered by these interactions of SH2 and SH3 domains is limited and not sufficient to enforce mutual exclusivity in RTK-mediated signaling. This may explain the current lack of success in pharmaceutical intervention to inhibit the interactions of these domains when they are responsible for aberrant signaling and the resulting disease states such as cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D055232:Proline-Rich Protein Domains; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013816:Thermodynamics; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D010455:Peptides; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases