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Structure[edit]

All four ErbB receptor family members are nearly same in the structure having single-chain of modular glycoproteins.[1] This structure is made up of an extracellular region or ectodomain or ligand binding region that contains approximately 620 amino acids, a single transmembrane-spanning region containing approximately 23 residues, and an intracellular cytoplasmic tyrosine kinase domain containing up to around 540 residues.[1][2][3] The extracellular region of each family member is made up of four subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region and these CR domains contain disulfide modules in their .tructure as 8 disulfide modules in CR1 domain, whereas 7 modules in CR2 domain.[1] These subdomains are shown in blue (L1), green (CR1), yellow (L2), and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV, respectively.[2][4][5] The intracellular/cytoplasmic region of the ErbB receptor comprises of mainly three subdomains: A juxtamembrane with approximately 40 residues, a kinase domain containing approximately 260 residues and a C-terminal regulatory region with around 232 residues.[1]

The figure below shows the tridimensional structure of the ErbB family proteins, using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4):[6][7][8][9]

Comparison of ErbB extracellular domain structures

ErbB and Kinase activation[edit]

The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher-order oligomers upon activation by a subset of potential growth factor ligands.[10] There are 11 growth factors that activate ErbB receptors.

The ability ('+') or inability ('-') of each growth factor to activate each of the ErbB receptors is shown in the table below:[11]

A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer (as shown) activates the kinase at the bottom of each dimer (Zhang et al., Cell v. 125, pp. 1137-1149, 2008). The cluster was identified with the ProtCID database. The image was made with PyMOL.
Ligand Receptor
ErbB-1 ErbB-2 ErbB-3 ErbB-4
EGF + - - -
TGF-α + - - -
HB-EGF + - - +
amphiregulin + - - -
betacellulin + - - +
epigen + - - -
epiregulin + - - +
neuregulin 1 - - + +
neuregulin 2 - - + +
neuregulin 3 - - - +
neuregulin 4 - - - +

The dimerization occurs after ligand bind to the extracellular domain of the ErbB monomers and monomer-monomer interaction establishes activating the activation loop in a kinase domain, that activates the further process of transphosphorylation of the specific tyrosine kinases in the kinase domain of ErbB's intracellular part.[12][2][13] It is a complex process due to the domain specificity and nature of the members of ErbB family.[14] Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases.[12] ErbB2 has no known binding ligand and absent of an active kinase domain in ErbB3 make this duo preferable to form heterodimers & share each other's active domains to activate transphosphorylation of the tyrosine kinases.[12][13][15][16] The specific tyrosine molecules mainly trans or auto-phosphorylated are at the site Y992, Y1045, Y1068, Y1148, Y1173 in the tail region of the ErbB monomer.[3] For the activation of kinase domain in the ErbB dimer, asymmetric kinase domain dimer of the two monomers is required with the intact asymmetric (N-C lobe) interface at the site of adjoining monomers.[3] Activation of the tyrosine kinase domain leads to the activation of the whole range of downstream signaling pathways like PLCγ, ERK 1/2, p38 MAPK, PI3-K/Akt and more with the cell.[13][14]

When not bound to a ligand, the extracellular regions of ErbB1, ErbB2, and ErbB4 are found in a tethered conformation in which a 10-amino-acid-long dimerization arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerization arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible.[11] The consequence of ectodomain dimerization is the positioning of two cytoplasmic domains such that transphosphorylation of specific tyrosine, serine, and threonine amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within the cytoplasmic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerization.[17][18][19] Although a number of potential phosphorylation sites exist, upon dimerization only one or much more rarely two of these sites are phosphorylated at any one time.[17]

  1. ^ a b c d Burgess, Antony W.; Cho, Hyun-Soo; Eigenbrot, Charles; Ferguson, Kathryn M.; Garrett, Thomas P. J.; Leahy, Daniel J.; Lemmon, Mark A.; Sliwkowski, Mark X.; Ward, Colin W. (2003-09-01). "An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors". Molecular Cell. 12 (3): 541–552. ISSN 1097-2765. PMID 14527402.
  2. ^ a b c Schlessinger, Joseph (2002). "Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor". Cell. 110 (6): 669–672. doi:10.1016/s0092-8674(02)00966-2.
  3. ^ a b c Zhang, Xuewu; Gureasko, Jodi; Shen, Kui; Cole, Philip A.; Kuriyan, John (2006-06-16). "An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor". Cell. 125 (6): 1137–1149. doi:10.1016/j.cell.2006.05.013. ISSN 0092-8674. PMID 16777603.{{cite journal}}: CS1 maint: date and year (link)
  4. ^ Garrett TP, McKern NM, et al. (2002). "Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α". Cell. 110 (6): 763–773. doi:10.1016/S0092-8674(02)00940-6. PMID 12297049.
  5. ^ Ward CW.; Lawrence M.C.; et al. (2007). "The insulin and EGF receptor structures: new insights into ligand-induced receptor activation". Trends Biochem. Sci. 32 (3): 129–137. doi:10.1016/j.tibs.2007.01.001. PMID 17280834.
  6. ^ Cho HS; Leahy DJ. (2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–1333. doi:10.1126/science.1074611. PMID 12154198.
  7. ^ Ferguson KM, Berger MB, et al. (2003). "EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization". Mol. Cell. 11 (2): 507–517. doi:10.1016/S1097-2765(03)00047-9. PMID 12620237.
  8. ^ Franklin MC, Carey KD, et al. (2004). "Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex". Cancer Cell. 5 (4): 317–328. doi:10.1016/S1535-6108(04)00083-2. PMID 15093539.
  9. ^ Bouyain S, Longo PA, et al. (2005). "The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand". Proc. Natl. Acad. Sci. USA. 102 (42): 15024–15029. doi:10.1073/pnas.0507591102. PMC 1257738. PMID 16203964.
  10. ^ Garrett TP, McKern NM, et al. (2002). "Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α". Cell. 110 (6): 763–773. doi:10.1016/S0092-8674(02)00940-6. PMID 12297049.
  11. ^ a b Linggi, B.; Carpenter, G. (2006). "ErbB receptors: new insights on mechanisms and biology". Trends Cell Biol. 16 (12): 649–656. doi:10.1016/j.tcb.2006.10.008. PMID 17085050.
  12. ^ a b c Akhtar, Saghir; Chandrasekhar, Bindu; Attur, Sreeja; Dhaunsi, Gursev S.; Yousif, Mariam H. M.; Benter, Ibrahim F. (2015-01-01). "Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor". PloS One. 10 (11): e0141657. doi:10.1371/journal.pone.0141657. ISSN 1932-6203. PMC 4633289. PMID 26536590.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ a b c Ceresa, Brian P.; Vanlandingham, Phillip A. (2008-01-01). "Molecular Mechanisms that Regulate Epidermal Growth Factor Receptor Inactivation". Clinical Medicine. Oncology. 2: 47–61. PMID 21892266.{{cite journal}}: CS1 maint: date and year (link)
  14. ^ a b Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P.; Haridas, Dhanya; Jain, Maneesh; Ganti, Apar K.; Batra, Surinder K. (2012-01-01). "Targeting the EGFR signaling pathway in cancer therapy". Expert Opinion on Therapeutic Targets. 16 (1): 15–31. doi:10.1517/14728222.2011.648617. ISSN 1744-7631. PMID 22239438.{{cite journal}}: CS1 maint: date and year (link)
  15. ^ Henriksen, Lasse; Grandal, Michael Vibo; Knudsen, Stine Louise Jeppe; van Deurs, Bo; Grøvdal, Lene Melsæther (2013-01-01). "Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands". PloS One. 8 (3): e58148. doi:10.1371/journal.pone.0058148. ISSN 1932-6203. PMID 23472148.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: unflagged free DOI (link)
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  17. ^ a b Wu SL, Kim J, et al. (2006). "Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using Extended Range Proteomic Analysis (ERPA)". Mol. Cell Proteomics. 5 (9): 1610–1627. doi:10.1074/mcp.M600105-MCP200. PMID 16799092.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1 (2005.0008): 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
  19. ^ Jorissen RN, Walker F, et al. (2003). "Epidermal growth factor receptor: mechanisms of activation and signalling". Exp. Cell Res. 284 (10): 31–53. doi:10.1016/S0014-4827(02)00098-8. PMID 12648464.
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