Protein scaffolding

AKAPs are a diverse family of about 75 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins to cellular compartments and thereby limit and integrate cellular signalling processes at specific sites. This compartmentalization of signalling by AKAPs contributes to the specificity of a cellular response to a given external stimulus (e.g. a particular hormone or neurotransmitter). 

AChE-R (in purple) Naturally rare, stress-induced variant, which lacks a hydrophobic domain and is incapable of binding to ColQ or PRiMA. Therefore, it remains soluble, and its secreted form shows greater mobility than AChE-S. AChE-R can intra-cellularly interact through its C-terminal tail with the Protein Kinase C Receptor RACK1, a scaffold protein which modifies multiple cellular processes. 

Numerous protein phosphatases are targeted to their substrates and regulators through the interaction with specific scaffolding proteins. Some of these anchoring proteins bind both, kinases and phosphatases. This applies to ser/thr protein phosphatases as well as to tyrosine phosphatases. 

SARA is a scaffolding protein that regulates the subcellular localization of inactivated R-Smads, potentially scaffolding the TGF-P receptor kinase to the Smad 2 substrate. Filamins are a family of actin polymerization proteins that also form scaffolds for a range of signaling proteins including SAP kinases such as MKK-4, small GTPases Rho and Ras, as well as Smad 2 and Smad 5. 

The 4F complex is particularly important in controUing the rate of protein translation. As described above, 4F is a complex consisting of 4E, which binds to the m G cap strucmre at the 5 end of the mRNA, and 4G, which serves as a scaffolding protein. In addition to binding 4E, 4G binds to elF-3, which hnlcs the complex to the 40S ribosomal subunit. It also binds 4A and 4B, the ATPase-hehcase complex that helps unwind the RNA (Figure 38—7). 

Saez ET, Pehar M, Vargas MR, Barbeito L, Maccioni RB (2006) Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75NTR-dependent tau hyperphosphorylation in cultured hippocampal neurons. J Neurosci Res 84 1098-1106 Sala C, Roussignol G, Meldolesi J, Fagni L (2005) Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca homeostasis at dendritic spines in hippocampal neurons. J Neurosci 25 4587 592 Santello M, Volterra A (2008) Synaptic modulation by astrocytes via Ca(2-l-)-dependent glutamate release. Neuroscience 158 253-9... 

Datta A, Stone MJ. Soluble mimics of a chemokine receptor chemokine binding by receptor elements juxtaposed on a soluble scaffold. Protein Sci 2003 12 2482-91. 

As described in more detail below, agonist binding will lead to signaling as well as phosphorylation of Ser and Thr residues, especially, but also, in selected cases, Tyr residues located in intracellular loop-3 and in the C-terminal extension. This post-translational modification alters the affinity of the receptor for various intracellular proteins, including arrestin, which sterically prevents further G-protein binding and functions as an adaptor protein. Also, interaction with other types of scaffolding proteins such as PSD-95-like proteins, is influenced by the phosphorylation state of the receptor. 

For family C receptors, the importance of and structural basis for interaction with intracellular adaptor or scaffolding proteins have been characterized in great detail, just as the issue of dimer formation is rather clear for these receptors. The main family of adaptor proteins, which ensures the cellular targeting and correct signaling function for the metabotropic glutamate receptors, appear... 

However, not all proteins proceed directly to their eventual destination. Some proteins relocate from one plasma membrane compartment to another by means of trans-cytosis. Transcytosis involves endocytosis of selected proteins in one membrane compartment, followed by subsequent transport through early endosomes to recycling endosomes and finally translocation to a different membrane compartment, for example from the apical to the basolateral surfaces. Sorting at the TGN and endo-some recycling steps appear to have a primary role in the steady state distribution of proteins in different plasma membrane domains [47], However, selective retention of proteins at the plasma membrane by scaffolding proteins or selective removal may also contribute to normal distributions. Finally, microtubule-motor regulatory mechanisms have been discovered that might explain the specific delivery of membrane proteins to discrete plasma membrane domains [48]. 

A major scaffolding protein of the PSD is PSD95. Two N-terminal cysteines of this protein bind palmitic acid residues, which anchor PSD95 to lipid rafts [30], PSD95 contains several domains that bind other proteins three so-called PDZ domains (short for PSD95/disc large/zona occludens-1), a src homology (SH3) domain, and a gua-nylate kinase (GK) domain. This family of proteins are... 

It is noteworthy that Src-induced increase in NR1-NR2A receptor activity is promoted by the coexpression of postsynaptic density protein known as PSD-95 [37]. PSD-95 is a scaffolding protein consisting of multiple protein-protein interaction domains - three N-terminal PDZ domains, an SH3 domain and a C-terminal guanyl-ate kinase domain. The first two PDZ domains interact with the NR2 C-terminal tails while the third PDZ domain... 

Of the seven mapped genes underlying Usher I, five have been identified. These included cadherin-23 and myosin-7a, both described above, harmonin and SANS, both scaffold proteins, and protocadherin-15, another member of the cadherin superfamily. Biochemical evidence and phenotypic similarity suggests that these proteins may assemble into a complex [29], although conclusive evidence for such a complex is lacking. 

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