Tyrosine extracellular region

Figure 10.7 The EGF receptor. The N-terminal, extracellular region of the receptor contains 622 amino acids. It displays two cysteine-rich regions, between which the ligand-binding domain is located. A 23 amino acid hydrophobic domain spans the plasma membrane. The receptor cytoplasmic region contains some 542 amino acids. It displays a tyrosine kinase domain, which includes several tyrosine autophosphorylation sites, and an actin-binding domain that may facilitate interaction with the cell cytoskeleton...

Both receptors have seven immunoglobulin-like domains in their extracellular region, a single-membrane-spanning domain, and an intracellular split tyrosine kinase domain... 

Fig. 1. Domain architecture of ErbB receptors. ErbB receptor extracellular regions are composed of four subdomains arranged as a tandem repeat of two types of domains. Two domain nomenclatures have been proposed (Bajaj et al., 1987 Lax et al., 1988 Ward et al., 1995). The domains in order from the N-terminus are referred to as domain I (El), II (CRl), III (L2), and IV (CR2). Domains I and III are homologous domains III and IV are homologous. The extracellular region is followed by a single membrane-spanning region, a cytoplasmic tyrosine kinase, and variable length tail that harbors several phosphorylation sites.

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

All receptors of the EGF family have two cysteine-rich clusters in the extracellular region and a tyrosine kinase domain in the cytoplasmic part. Autophosphorylation sites are in the C-terminal regions of the cytoplasmic domain. On activation, five tyrosines are... 

It remains unclear whether such approaches are truly general, in particular for proteins such as receptors that span different cellular compartments. For example, some receptor tyrosine kinases contain a kringle domain in their extracellular regions. Would such protocols predict common functions for intracellular tyrosine kinases and extracellular kringle-containing proteins, such as those of the hlood coagulation pathway Nevertheless, it is apparent that considerable functional constraints exist for domains to co-occur and that domain combinations are often very limited. 

The cytoplasmic domains of all of these receptors have an intrinsic protein tyrosine kinase activity, and all the receptors have hydrophobic transmembrane sequences. Their extracellular regions are more variable in stmcture. Depending on the receptor, they may contain a range of domains, including (1) immrmoglobulin domains, (2) cysteine-rich motifs, (3) fibronectin type III repeats, and (4) EGF motifs. These can be present singly or in different combinations. Growth factor receptors are therefore examples of mosaic proteins. 

Preobrazhensky AA, Dragan S, Kawano T, et al. Monocyte chemotactic protein-1 receptor CCR2B is a glycoprotein that has tyrosine sulfation in a conserved extracellular N-terminal region. J Immunol 2000 165 5295-303. 

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