Phosphorylated kinase inducible domain

Coupled folding and binding is a frequent theme in the field of intrinsically disordered proteins (see Chap. 6). One of the earliest examples of this phenomenon was the interaction of the phosphorylated kinase-inducible domain (pKID) of the transcription factor CREB with the KIX domain of the transcriptional coactivator CBP. Free pKID is unfolded in solution [21], but folds into an orthogonal pair of helices, aA and aB, upon binding to the folded KIX domain (Fig. 1.5) [23]. We have recently posed the question, what is the... 

Fig. 6.4. Illustration of the unfolded nature of the phosphorylated kinase-inducible domain (pKID) of CREB (left) and its conformation after folding upon binding to the KIX domain of CBP (right). The mechanism of this process has recently been elucidated by NMR [28] and is discussed more fully in Chap. 1 (Wright). Adapted by permission from [5] (Macmillan Publishers Ltd., copyright 2005)...

Figure 31.32. Domain Structure of CREB-Binding Protein (CBP). The CREB-binding protein includes at least three types of protein-protein interaction domains in addition to a histone acetyltransferase domain that lies near the carboxyl terminus. The kinase-inducible interaction (KIX) domain interacts specifically with a region of CREB in its phosphorylated form.

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

Chen et al. [62] have proposed that protein kinase C is involved in the fi receptor desensitization since activators of this enzyme potentate fi receptor uncoupling from the K+ channel. The fi receptor has consensus protein kinase C phosphorylation sites in its intracellular domains [8]. Arden et al. [88] have reported that morphine can induce the phosphorylation of the cloned fi receptor and Zhang et al. [64] have reported that activators of protein kinase C can induce the phosphorylation of the ft receptor. 

The exact molecular mechanisms by which TNF-induced signal transduction are mediated remain to be characterized in detail. Oligomerization of the receptors is often followed by their phosphorylation, most likely by accessory kinases that associate with the intracellular domain of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55 and TNF-R75 have also been established. Following clustering of the TNF receptors, these... 

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