21.5:
Assembly of Signaling Complexes
Signaling complexes are protein clusters assembled on a receptor's intracellular docking sites. This assembly aids signal transduction by grouping molecules into a single location.
Signaling complexes can be assembled in different ways. For example, some signals induce phosphorylation of either a receptor or phosphoinositides in the plasma membrane, creating a temporary docking site for signaling complex assembly.
In other cases, a large scaffold protein may help pre-assemble the signaling proteins on an inactive receptor. Scaffolds hold signaling proteins in close proximity, ensuring a rapid and selective response to the extracellular signal.
The specificity of protein-protein and protein-phospholipid interactions in the signaling complexes is controlled by multiple interaction domains in the signaling proteins.
The Src homology 2 or SH2 and phosphotyrosine-binding or PTB domains in the docking proteins bind to the phosphorylated tyrosines. In contrast, the Src homology 3 or SH3 domain binds to the proline-rich sequences.
The pleckstrin homology or PH domain recognizes the charged head groups of phosphoinositides allowing proteins to dock on the plasma membrane.
21.5:
Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences, including the phosphotyrosine motifs (SH2) and phosphotyrosine-binding (PTB) domains or proline proline-rich sequences (SH3 domains).
SH2 domains are commonly found in a diverse group of cytoplasmic polypeptides that are targets of receptor tyrosine kinases (RTK) and in receptors for antigens, cytokines, and extracellular matrix components. SH2 domains also recognize three and five residues immediately C-terminal to the phosphotyrosine, thus influencing binding affinity and specificity. The specificity and affinity can be further increased by the ability of SH2 domains to act in synergy with additional interaction domains such as two tandem SH2 domains or an SH2 and SH3 domain. For example, the Grb2 adaptor protein contains an SH2 and an SH3 domain that link a single phosphotyrosine site to multiple intracellular relay proteins. Consequently, it can regulate both MAP kinase and PI3 kinase pathways.
Scaffold proteins
Scaffold proteins serve as docking sites for multiple protein partners in a cascade. The protein partners are closely spaced to cut down the time required for proteins to find their interacting partners in a cascade. An activated membrane receptor sends messages to the protein scaffolds to get loaded with the required signaling proteins. In other cases, signaling proteins are pre-anchored to the scaffold before receiving a message from the receptor to increase efficiency.
Scaffolds associated with G-protein-coupled receptors (GPCRs) interact through their GPCR PDZ domains. This domain facilitates GPCR interactions with the carboxyl-termini of intracellular signaling proteins. Ligand binding causes a change in receptor conformation leading to enhanced interaction of scaffold proteins with G-proteins and GPCRs. One of the best-characterized scaffold families interacting with GPCRs and G proteins is the β-arrestins.