Effectors domain

So far ten catalytically active caspases have been reported in mouse (caspase-1, -2, -3, -6, -7, -8, -9, -11, -12,-14) and eleven in human (caspase-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -14) (Fig. 1). Caspases are expressed as inactive proenzymes that contain an amino-terminal prodomain of variable length followed by two domains with conserved sequences a large subunit ( 20 kDa, p20) and a small carboxy-terminal subunit ( 10 kDa, plO). Caspases can be divided according to absence (-3, -6, -7, -14) or presence (-1, -2, -8, -9, -10, -11, -12) of an extended prodomain containing protein-protein interaction motifs belonging to the death domain (DD) superfamily, in particular the death effector domains (DED) and the caspase activation and recruitment domains (CARD). 

ALT, alanine aminotransferase ASC, apoptosis-associated speck-like protei containing a CARD AST, aspartate aminotransferase CARD, caspase activation and recruitment domains CD, Crohn s disease COP, CARD-only protein DD, death domain DED, death effector domains DIABLO, direct LAP-binding protein with low pi... 

Death domain (DD) superfamily consists of structurally related homotypic interaction motifs of approximately 90 amino acids. The motifs are organized in six antiparallel amphipathic a-helices, the so-called DD fold. The four members of the super family are the death domain (DD), the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the Pyrin domain. All are important mediators for the assembly of caspase activating complexes. 

Receptors that Couple to an Intramolecularly Linked Effector Domain... 

Receptors permanently linked to an effector consist of proteins with an extracellular ligand-binding receptor domain and a signal-generating effector domain (Fig. 1). Most of these receptors are composed of two to five structurally related or identical subunits. Effectors can be enzymes or ion channels whose activities are stimulated by agonist binding without significant delay. 

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. 

Growth-Arrest-Specific protein 2 Domain Gastrin/cholecystokinin/caerulein family Dynamin GTPase effector domain Gelsolin homology domain G protein y subunit-like motifs Glycoprotein hormone a chain homologs... 

Protein receptors for endogenous ligands (e.g., hormones, neurotransmitters) share some common properties. They contain a ligand-binding domain, where the hormone or neurotransmitter attaches, and an effector domain, which translates the binding into some from of action. 

Figure 17.12 Structure of an antibody. V-region is the variable region and C-region is the constant region. Fc is the portion of the antibody that contains the effector domains. S-S is the suLphydryl Link between the chains. NH3 represents the amino terminus of each chain.

Fig. 5 Alignment of the effector domains H-Ras, AGSl, and Rhes. The asterisks indicate identity...

Fig. 1.21. Structural and functional principles of transcription activators. Typical transcription activators of encaryotes possess a DNA-binding domain, an effector domain and a transactivating domain. An incoming signal is registered by the effector domain and transformed into a change in affinity for DNA. In the active state, the transcription activator is capable of binding to its cognate DNA-binding element. Protein-protein interactions with the transcription apparatus bound to the promoter mediate a stimnlation of transcription initiation.

Fig. 7.12. Functional domains or the MARCKS proteins. Linear representation of the characteristic domains of the MARCKS proteins. The Ser phosphorylation sites in the effector domain are underlined. The function of the MH2 domain is nnknown.

The MARCKS proteins are acidic proteins with a high content of the amino acids Ala, Gly, Pro and Glu. An N-terminal domain carries a lipid anchor in the form of myristinic acid, from which it is assumed that it mediates the association with the membrane. A basic effector domain is important for regulation of the MARCKS proteins a binding site for Ca calmoduhn and the phosphorylation site for protein kinase C are located in this domain (see Fig. 7.12). 

The L2 loop (residues 32-37) corresponds to switch I of the Ga-subimits (see 5.5.6) it is known as the effector loop. It is an important part of the effector domain of the Ras protein, and signals are received and passed on via this domain. 

It is not surprising that residues corresponding to switch I and switch II, which define the conformational differences between the inactive GDP form and the active GTP state of Ras, are involved in recognition of the Ras effectors, the immediate downstream components in the Ras signaling pathway (see 9.6 and 9.7). Residues 32-40 comprise the core Ras effector domain, which is essential for all effector interactions. 

The structure of the complex indicates a specific interaction between P-sheet structures of Raf kinase and structural elements of RaplA protein belonging to the switch I region, which are thus part of the RaplA protein effector domain. Since RaplA protein has a very similar structure to Ras protein, it is assumed that Ras protein also interacts with Raf kinase via its switch I region. 

Activation of the caspases requires the help of a number of cofactors that are also known as activators or adaptors. Different cofactors are involved depending on the trigger mechanism of caspase activation. A central function of the cofactors is to bring about aggregation and thus activation of the procaspases. This occurs by specific protein-protein interactions with the help of common structural motives. Examples of such motives are the death domains (DD), death effector domains (DED) and the caspase recruitment domains (CARD), which all have a similar structure of six a-heh-ces. 

In the case of the death receptor Fas (see 15.4), activation of the caspase involves a protein that interacts with the cytoplasmic part of the receptor and is known as FADD protein (Fas-associated death domain). The FADD protein has distinct structural motives that mediate specific interactions with other proteins. It interacts via the death domain with the receptor and via the death effector domain with the corresponding caspase (here caspase 8). 

Binding of the ligand of the Fas receptor triggers clustering of the receptor and association of the cofactor FADD (fas-assodated protein with death domain) which interacts with the receptor via its death domain (DD). Procaspase 8 binds to FADD via a common DED (death effector domain) motif and is thereby also recruited into the Fas-receptor associated complex. Due to the clustering of the proteins, proximity-induced cleavage of procaspase 8 to the mature initiator caspase 8 takes place. This activates the effector caspases and triggers cell death. 

There are both functional and structural domains. A functional domain may consist of one or more structural domains. A functional domain is a functionally autonomous region of the molecule. In the case of the IgG, the Fab portion is the functional antigen recognition domain while the Fc region is an effector domain. Structural domains are geometrically separate. 

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