Noncatalytic domains

Under physiological conditions, NRPTKs are highly specific in directing tyrosine phosphorylation toward appropriate substrates. This specificity relies on the intrinsic predilection of the catalytic domain towards specific amino acid sequences within protein substrates. In addition, noncatalytic domains, e.g., SH2, SH3 and PH domains of NRPTKs, distribute these kinases to the subcellular region where appropriate substrates are in proximity or abundance, thus favoring phosphorylation of these proteins rather than other substrates. 

Zhou X, Richon VM, Rifkind RA, Marks PA (2000) Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Proc Natl Acad Sci USA 97(3) 1056-1061 Zhou X, Marks PA, Rifkind RA, Richon VM (2001) Cloning and characterization of a histone deacetylase, HDAC9. Proc Natl Acad Sci U S A 98(19) 10572-10577 Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23 217-247... 

Sadowski, I., Stone, J. C., and Pawson, T. (1986). A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag- s, Mol Cell Biol 6, 4396-408. 

Schaller, M.D. Borgman, C.A. Parson,s, J.T. Autonomous expression of a noncatalytic domain of the focal adhesion-associated protein tyrosine kinase ppl25FAK. Mol. Cell. Biol., 13, 785-791 (1993)... 

Noncatalytic phosphotyrosine binding (PTB) domains are 100-150 residue modules, which bind Asn-Pro-X-Tyr motifs. PTB-domain binding specificity is determined by residues at the amino-terminal side of the phosphotyrosine. In most cases, the tyrosine residue must be phosphorylated in order to mediate binding. PTB domain containing proteins are often found in signal transduction pathways. 

The identification of noncatalytic regulatory domains referred to as Src homology (SH) domains has been rapidly advanced over recent years as a critical link... 

The bcf complexes form dimers in the membrane with molecular masses of approximately 480 kDa (mitochondria) and 130 kDa (bacteria), respectively. Each monomer has 10-13 membrane spanning helices, depending on the number of noncatalytic subunits. The membrane spanning helices of cytochrome b are in the center of the structure and form the dimer interface while the other membrane spanning helices are located around cytochrome b. Cytochrome c and the Rieske iron sulfur protein both have water soluble domains containing the redox centers, heme ci and the [2Fe-2S] cluster, respectively. These domains are at the outside of the iimer mitochondrial membrane, i.e., in the intermembrane space, and bound to the membrane via membrane spanning helices acting as membrane anchors. 

Fig. 11. The lipase-procolipase complex details are as in Figs. 1-3 the procolipase molecule is the more darkly shaded molecule, and is bound to the noncatalytic C-terminal domain of hPL.

The metzincin catalytic domain consists of a flat surface within a small cleft within which peptide substrates bind and are hydrolyzed (Fig. 8.2a). In astacins, the catalytic domain is stable, but adamalysins require a calcium ion to stabilize the flat surface of the domain above the cleft. Matrilysins require two calcium ions and a second, noncatalytic zinc ion to stabilize this domain (Fig. 8.3). Table 8.3 reviews the roles of specific metal ions that participate in the various stages of collagen processing discussed in this chapter and Chap. 7. 

The presence of two coenzyme-binding sites is unexpected since they cannot be inferred solely from the crystal structure of CPR. Kinetic studies with wild t) e and W676H CPR at different concentrations of NADPH have, however, provided further support for the existence of two sites The rate of flavin reduction in the isolated FAD domain and CPR increases as NADPH is decreased from molar excess to stoichiometric concentrations. At stoichiometric concentration, the second noncatalytic site is predominantly vacant and the partial inhibition on the rate of flavin reduction from the catalytic site is therefore relieved (Figure 4.9). Occupation of the noncatalytic site occurs at NADPH concentrations in excess of the enzyme concentration, and impairs NADP" " release from the catalytic site. This in turn partially inhibits flavin reduction, the rate of which is gated by NADP release. Preincubation of the enzyme with a stoichiometric amount of adenosine 2, 5 -diphosphate does not lead to inhibition of the flavin reduction rate. We infer that the binding of adenosine 2, 5 -diphosphate prevents NADPH from binding to the noncatalytic site. This observation also suggests that it is the nicotinamide-ribose-phosphate portion of NADPH bound at the second site that hinders NADP" release from the catalytic site. Clearly, these new... 

The protein p56 lymphoid T-cell tyrosine kinase (Lck) is predominantly expressed in T lymphocytes where it plays a critical role in T-cell-mediated immune response. Lck participates in phosphotyrosine-dependent protein-protein interactions through its modular binding unit, the Src homology-2 (SH2) domain. SH2 domains are noncatalytic modules of about 100 amino acid residues that play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. Failure of the p5 6 Lck S H 2 domain to bind to immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 hampers the T-cell receptor (TCR) proximal activation process and suppresses the downstream T-cell activation signaling cascades [143]. Small compounds that would be able to block Lck SH2 domain-dependent protein-protein interactions could find therapeutic utility as immunosuppressants and in the treatment of T-cell leukemias, lymphomas, and autoimmune diseases such as rheumatoid arthritis. 

A -glycosylation sites in human proteins and 0-P-GlcNAc/phosphorylation sites respectively. CAZY (http //afmb.cnr-mrs.lr/CAZY/) is a comprehensive database for carbohydrate active enzymes (CAZYmes). CAZYmes are classified into seqnence-derived fanulies (Davis and Henrissat, 2002). They are modular, consisting of one or more catalytic domains in harness with many noncatalytic modules, which often posses a carbohydrate binding functionality. Active-site residues, molecular mechanisms and 3D structures are all conserved within families. 

Studies to search for PolK-interacting proteins revealed that PoIk interacts with a G-terminal region of REVl (Guo et al, 2003 Ohashi et oL, 2004), which has been known to interact with REV7, the noncatalytic subunit of another TLS enzyme Pol (Murakumo et al., 2001). Interestingly, REVl has a BRGT domain near the N terminus, which may function as an interaction domain with another protein (for more details, see the chapter by Lawrence). Because the G-terminal region of REVl also interacts with Polr/ and Poh, it seems likely that REVl plays a key role, for example, as a scaffold protein in a multiprotein complex for TLS in vivo. 

A comparative modefing study of the three concepts (the two in Fig. 3.1 and the aforementioned i-CST in Fig. 3.15a) is presented next for H2/air combustion over platinum. The numerical model for the CST concept of Fig. 3.1A is shown in Fig. 3.3 and refers to a single channel with FeCr-aUoy walls. For the fuel-rich concept in Fig. 3.IB, the single-channel model with bypass air in Fig. 3.16A is adopted, whereas for the i-CST concept the model in Fig. 3.16B is employed (due to symmetry, only half the domains are shown in Fig. 3.16). In Fig. 3.16B, the initial channel length L=15 mm was chemically inert (noncatalytic), while the remaining 60 mm was coated with platinum. This approach allowed for the establishment of an upstream... 

---