Noncatalytic protein domains

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. 

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. 

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. 

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. 

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)... 

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. 

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