Ectodomain

APP undergoes proteolytic processing by several secretases. First, the bulk of the ectodomain needs to be removed by membrane-bound a- or (3-secretases leading to secreted forms of APP and membrane-bound C-terminal fragments a-CTF or (3-CTF, respectively. Regulated intramembrane proteolysis (RIP) of the (3-CTF by y-secretase occurs only after ectodomain shedding and releases the A(3 pqrtide from the membrane (Fig. 2). 

Thyrotropin (TSH) regulates the production and secretion of thyroid hormones as well as thyroid epithelial cell growth via the TSH receptor. The TSH receptor belongs to the family of G protein-coupled receptors. It is composed of 764 amino acids. The receptor contains a long hydrophilic region orientated towards the exterior of the cell (ectodomain), 7 hydrophobic transmembrane domains and a short cytoplasmic region. 

Karlsson GB, Halloran M, Schenten D, Lee J, Racz P, Tenner-Racz K, Manola J, Gelman R, Etemad-Moghadam B, Desjardins E, Wyatt R, Gerard NP, Marcon L, Margolin D, Fanton J, Axthelm MK, Letvin NL, Sodroski J (1998) The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian- human immunodeficiency virus-infected macaques. J Exp Med 188 1159-1171... 

Edwards TG, Wyss S, Reeves JD, et al. Truncation of the cytoplasmic domain induces exposure of conserved regions in the ectodomain of human immunodeficiency virus type 1 envelope protein. J Virol 2002 76(6) 2683-2691. 

Smalley DM, Ley K. L-selectin mechanisms and physiological significance of ectodomain cleavage. J Cell Mol Med 2005 9 255-266. 

Wu Q, Maniatis T. Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes. Proc Natl Acad Sci USA 2000 97[7] 3124-3129. 

Fig. 11.2. A donor dequenching experiment that demonstrates that extracellular domains of APP and LRP closely associated with one another. H4 cells were transfected with APP770 and LRP and immunolabeled with Fluorescein (A) and Cy3 (B), respectively. When the Cy3 is photobleached in the area marked by the white rectangle, the signal from fluorescein increases (C), while the signal from Cy3 disappears (D). The increase in donor fluorescence is calculated to be 51%, which shows that the ectodomains of APP770 and LRP, are in close proximity and therefore likely to be interacting. This result has implications for the field of Alzheimer s disease research as it helps elucidate the nature of APP processing into amyloid-/ [50],...

Boggon, T. J., Murray, J., Chapuis-Flament, S., Wong, E., Gumbiner, B. M. and Shapiro, L. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296(5571) 1308-1313, 2002... 

Zhang, Z. et al., Inhibition of TNF-alpha processing and TACE-mediated ectodomain shedding by ethanol, JLeukoc. Biol., 67, 856, 2000. 

Weissenhorn, W., Galder, L.J., Dessen, A., Laue, T., Skehel,J. J., and Wiley, D. C. (1997). Assembly of a rod-shaped chimera of a trimeric GCN4 zipper and the HIV-1 gp41 ectodomain expressed in Escherichia coli. Proc. Natl. Acad. Sri. USA 94, 6065-6069. 

AP has a very effective binding domain for copper in its N-terminal domain and can bind copper in nanomolar amounts (Figure 18.15). It is unclear whether APP or AP when associated with copper, are in fact neuronal metallochaperones. Knock out and knock in mice for APP show that in the former, cerebral cortex copper levels are increased, whereas in the latter reduced copper levels were found. Copper was also influential in APP processing in the cell copper will reduce levels of Ap and cause an increase in the secretion of the APP ectodomain. 

Kobe B, Center RJ, Kemp BE, Poumbouris P. 1999. Crystal structure of human T cell leukemia virus type 1 gp21 ectodomain crystallized as a maltose binding protein chimera reveals structural evolution of retroviral transmembrane proteins. Proc Natl Acad Sci USA 96 4319-4324. 

Over the last decade, a substantial amoimt of information about properties and spatial structures of different representatives of the TGF- superfamily, both free and in complexes with ectodomains of their transmembrane receptors, have been accumulated. Consequently, a number of important steps towards understanding initiation and actuation of TGF-b signahng, as well as the biological response to the signal transduction and interplay with other signaling pathways have been made [2,12,18,46-50]. 

Fig. 2 Ribbon presentations of available crystal structures of TGF- 3 ligands, both free (a) and in complexes with their T 3R1 (b) and T 3R11 (c) receptors. The/ro t and top views are shown. The TGF- 3 ligands are shown in dark gray. The ectodomains of TflRl and TpRll receptors are highlighted in light gray...

According to our prior data obtained for TGF-P3 [14] (Fig. 6c,d). the intersubunit interface and the a3 helix in particular are flexible and therefore the tubes are not always fully formed. The unfolded state of this part of the TGF-b3 dimer was observed for its complex with two ectodomains of the type II... 

Nishi, S., Nakabayashi, K., Kobilka, B., and Hsueh, A. J. (2002). The ectodomain of the luteinizing hormone receptor interacts with exoloop 2 to constrain the transmembrane region Studies using chimeric human and fly receptors. /. Biol. Chem. 277, 3958-3964. 

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