Domain extracellular

Leucine residues 2, 5, 7, 12, 20, and 24 of the motif are invariant in both type A and type B repeats of the ribonuclease inhibitor. An examination of more than 500 tandem repeats from 68 different proteins has shown that residues 20 and 24 can be other hydrophobic residues, whereas the remaining four leucine residues are present in all repeats. On the basis of the crystal structure of the ribonuclease inhibitor and the important structural role of these leucine residues, it has been possible to construct plausible structural models of several other proteins with leucine-rich motifs, such as the extracellular domains of the thyrotropin and gonadotropin receptors. 

Figure 13.1 The basic organization of a membrane receptor molecule consists of an extracellular domain, a transmembrane region, and an intracellular domain.

Figure 13.19 Ribbon diagram of the stmcture of the extracellular domain of the human growth hormone. The hormone-binding region is formed by loops (yellow) at the hinge region between two fibronectin type III domains. (Adapted from J. Wells et al., Annu. Rev.

Figure 13.20 Ribbon diagram of the structure of a 1 2 complex between the human growth hormone and the extracellular domains of two receptor molecules. The two receptor molecules (blue) bind the hormone (red) with essentially the same loop regions (yellow).

The prolactin receptor, PER, which regulates milk production in mammals, belongs to the same receptor class as the growth hormone receptor. In addition to binding the hormone prolactin, PER also binds and is activated by growth hormone. The extracellular domain of PER forms a very stable 1 1 complex with growth hormone in solution this complex has been crystallized and its structure determined (Figure 13.21). We shall compare this structure with the 1 2 complex of the same hormone with GHR. 

De Vos, A.M., Ultsch, M., Kossiakoff, A.A. Human growth hormone and extracellular domain of its receptor crystal structure of the complex. Science 255 306-312,... 

T-cell receptors (TCR) are heterodimeric transmembrane glycoproteins found exclusively in T cells, with extracellular domains that closely resemble antibody Fab structures. Each of the TCR a and p chains forms half of an extracellular antigen-binding domain, and in addition has one transmembrane... 

Figure 17.12 Ribbon diagram of EMPl bound to the extracellular domain of the erythropoietin receptor (EBP). Binding of EMPl causes dimerization of erythropoietin receptor. The x-ray crystal structure of the EMPl-EBP complex shows a nearly symmetrical dimer complex in which both peptide monomers interact with both copies of EBP. Recognition between the EMPl peptides and EBP utilizes more than 60% of the EMPl surface and four of six loops in the erythropoietin-binding pocket of EBP.

Heptahelical receptors, another name for 7 TM receptors or G-protein-coupled receptors. It refers to the motif of the helices of the protein crossing the cell membrane seven times to form intracellular and extracellular domains. 

Ca2+ sensing receptor, a member of G-protein coupled receptors, is composed of seven transmembrane spanning domains. The extracellular domain contains clusters of negatively charged amino acids sensing even small fluctuations of extracellular calcium. Mutations in this receptor cause inheritable hypo- and hypercalcemic syndromes. 

Cadherins (Calcium-dependent adhesion proteins) are transmembrane proteins, which consist of an extracellular domain composed of cadherin-repeats, a transmembrane domain, and a cytoplasmic domain that interacts with catenins and/or other cytoplasmic proteins. 

The extracellular domain of cadherins consists of a variable number of a repeated sequence of about 110 amino acids. This sequence is termed the cadherin repeat and resembles in overall structure, but not in sequence, the Ig like domains. The cadherin repeat is the characteristic motive common to all members of the cadherin superfamily. Classical and desmosomal cadherins contain five cadherin repeats, but as many as 34 repeats have been found in the FAT cadherin (see below). Cadherins are calcium-dependent cell adhesion molecules, which means that removal of Ca2+, e.g., by chelating agents such as EDTA, leads to loss of cadherin function. The Ca2+-binding pockets are made up of amino acids from two consecutive cadherin repeats, which form a characteristic tertiary structure to coordinate a single Ca2+ion [1]. 

The classical cadherins are translated as precursor because they are N-terminally cleaved to reveal the mature proteins. This processing is required to activate the cell adhesion function of cadherins. Cadherins interact in trans (i.e., from opposite cells) via the most N-terminal cadherin rqDeats. A short amino acid sequence within this repeat, histidine-alanine-valine (HAV), has been implicated in mediating cell-cell contacts as HAV peptides can disrupt cadherin-dependent cell adhesion. Besides the trans-interactions of cadherins, the extracellular domains are also capable of forming cis-dimers through lateral amino acid contacts between cadherin molecules on one cell. This dimerization again mainly involves the first cadherin repeat. A zipper model based on the pattern of alternating cis- and trans-dimers [1] for the adhesive interactions has been proposed. 

Several nonconventional cadherins that contain cadherin repeats have been described but they have specific features not found in the classical cadherins [1]. The cadherin Flamingo, originally detected in Drosophila, contains seven transmembrane segments and in this respect resembles G protein-coupled receptors. The extracellular domain of Flamingo and its mammalian homologs is composed of cadherin repeats as well as EGF-like and laminin motifs. The seven transmembrane span cadherins have a role in homotypic cell interactions and in the establishment of cell polarity. The FAT-related cadherins are characterized by a large number of cadherin repeats (34 in FAT and 27 in dachsous). Their cytoplasmic domains can bind to catenins. T- (=truncated-)cadherin differs from other cadherins in that it has no transmembrane domain but is attached to the cell membrane via a glycosylpho-sphatidylinositol anchor. 

Recombinant soluble TNF-RI-IgGl fusion protein Etanercept, Enbrel is a chimeric molecule consisting of the extracellular domain of the TNF receptor I (TNF-RI) and the Fc portion of human IgGl. Two Fc domains are bound to each other via disulfide bonds, thereby yielding dimers with two binding sites for the TNF trimer. Etanercept binds with high affinity to extracellular TNF and reduces TNF activity. Etanercept is not effective in Crohn s disease, possibly because it does not lead to destiuction of membrane TNF-a expressing cells. Indications and side effects are similar to those of Infliximab and Adalimumab. 

Frizzled (Fz) proteins comprise a family of seven-pass transmembrane receptors with a cysteine-rich extracellular domain. As a class, Fz proteins are structurally related to the superfamily ofheterotrimeric G-protein coupled receptors (GPCRs). Diere are 4 Fz genes in Drosophila and 10 in humans, with close orthologs... 

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