Effector proteins

Formation of a novel binding site novel complexes may be formed between a SUMOylated protein and an effector protein that contains a SUMO-interacting motif (SIM or SBM). Proteins that contain two binding sites, a SIM and a weak binding motif to protein X, will bind more strongly to this protein if it is SUMOylated (Fig. 3b). Short peptides that contain the hydrophobic core motif [V/I]-X-[V/I]-[V/I] or [V/I-[V/I]]-X-[V/I] can act as a SIM and bind to SUMO. This core is often flanked by acidic amino acids and/or serine residues. 

Transmembrane Signaling. Figure 2 Membrane topology of receptors that are associated with effector proteins. Upon binding to their cognate ligands (cyan), receptor proteins without intramolecularly linked effector domain couple via transducer proteins (yellow) to or directly recruit and activate effector proteins (red). Notch receptors release their transducer domains upon proteolytic cleavage, a, p and y stand for G-protein a-, p- and y-subunits, respectively. 

In general, the receptor-G-proteins complexes exchange bound GDP for GTP. In turn, the two, smaller subunits of the G-protein components of these complexes are released and the receptor protein dissociates. The remaining G-protein GTP complex then complexes with and activates a specific enzyme. It is very significant to note that G-proteins therefore have at least three specific binding sites (a) for nucleotides, (b) for a receptor protein, and (c) an effector protein. 

FIGURE 8.3 Domain organization of proteins that associate with phosphorylated tyrosine kinase (PTK)-containing receptors. Proteins that associate with tyrosine-phosphorylated receptors contain SH2 or PTB domains, which recognize specific amino-acid stretches in the vicinity of phosphorylated tyrosine residues. Unlike the enzymes, the adaptors lack intrinsic catalytic activity but serve to link phosphorylated receptors with other effector proteins. Some of the proteins presented in this figure are discussed in this chapter. 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

Bishop AL. Rho GTPases and their effector proteins. Biochem J 2000 348 241-255. 

I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway, in particular, effects mediated through its effector protein kinase B (PKB, also termed Akt three isoforms) ... 

Positive regulators (enhancers) Turn on transcription when a specific effector protein binds to a specific enhancer sequence in the DNA. 

The fluidity of lipid bilayers permits dynamic interactions among membrane proteins. For example, the interactions of a neurotransmitter or hormone with its receptor can dissociate a transducer protein, which in turn will diffuse to interact with other effector proteins (Ch. 19). A given effector protein, such as adenylyl cyclase, may respond differently to different receptors because of mediation by different transducers. These dynamic interactions require rapid protein diffusion within the plane of the membrane bilayer. Receptor occupation can initiate extensive redistribution of membrane proteins, as exemplified by the clustering of membrane antigens consequent to binding bivalent antibodies [8]. In contrast to these examples of lateral mobility, the surface distribution of integral membrane proteins can be fixed by interactions with other proteins. Membranes may also be partitioned into local spatial domains consisting of networks... 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Question marks indicate that the association between the particular G proteins and effector proteins shown in the table remains tentative. 

Tor several of the effector proteins listed, the functional regulation of the effector is mediated, in part or in full, by the [ly subunits associated with the indicated a subunit. 

Maintenance of organellar integrity Maintenance of ATP levels Maintenance of ion homeostasis Membrane surface blebbing Nuclear chromatin condensation/fragmentation Requires synthesis of death effector proteins Prevented by blocking steps in the death cascade Does not adversely affect neighbor cells... 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

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