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== Structure ==
== Structure ==
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ERBB receptors contain an extracellular domain (ECD), a transmembrane domain (TMD), an intracellular region that consists of a juxtamembrane domain (JMD), a kinase domain (KD) and a carboxy terminal tail domain (CTD) (Kovacs et al., 2015). The ECD is comprised of four subdomains (I-IV). In the absence of ligand, the ECD adopts an auto-inhibited tethered (closed) conformation that involves domain II and IV. Upon ligand binding between domains I and III, the dimerization arm in domain II is untethered, leading to receptor homo or heterodimerization, allosteric kinase activation, CTD phosphorylation and downstream signaling (Kovacs et al., 2015)<ref>DOI 10.1016/j.ccell.2018.09.010</ref>.
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ERBB receptors contain an extracellular domain (ECD), a transmembrane domain (TMD), an intracellular region that consists of a juxtamembrane domain (JMD), a kinase domain (KD) and a carboxy terminal tail domain (CTD) <ref>DOI 10.1146/annurev-biochem-060614-034402</ref>. The ECD is comprised of four subdomains (I-IV). In the absence of ligand, the ECD adopts an auto-inhibited tethered (closed) conformation that involves domain II and IV. Upon ligand binding between domains I and III, the dimerization arm in domain II is untethered, leading to receptor homo or heterodimerization, allosteric kinase activation, CTD phosphorylation and downstream signaling <ref>DOI 10.1146/annurev-biochem-060614-034402</ref><ref>DOI 10.1016/j.ccell.2018.09.010</ref>.
[[Image:Dg_sb_Figure1.jpg|frame|center|Full-length EGFR and its oligomerization states
[[Image:Dg_sb_Figure1.jpg|frame|center|Full-length EGFR and its oligomerization states
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A) A proposed composite model of full-length EGFR based on the structures of individual modules (PDB ID 3NJP for the extracellular module, PDB ID 2M20 for the transmembrane - JM-A helices, and PDB ID 2GS6 for the kinase domains). B) Schematics for possible oligomerization states of EGFR in cells. (Kovacs et al., 2015)
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A) A proposed composite model of full-length EGFR based on the structures of individual modules (PDB ID 3NJP for the extracellular module, PDB ID 2M20 for the transmembrane - JM-A helices, and PDB ID 2GS6 for the kinase domains). B) Schematics for possible oligomerization states of EGFR in cells. <ref>DOI 10.1146/annurev-biochem-060614-034402</ref>
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HER2 is an atypical member of the ERBB family, as its ECD adopts an untethered conformation constitutively (Roskoski, 2014). Unlike the other ERBB family members, HER2 does not have a ligand. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or EGFR to initiate cellular signaling, although HER2 homodimers capable of signaling have been reported in HER2 overexpressing cells (Brennan et al., 2000; Roskoski, 2014). <ref>DOI 10.1016/j.ccell.2018.09.010</ref>
HER2 is an atypical member of the ERBB family, as its ECD adopts an untethered conformation constitutively (Roskoski, 2014). Unlike the other ERBB family members, HER2 does not have a ligand. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or EGFR to initiate cellular signaling, although HER2 homodimers capable of signaling have been reported in HER2 overexpressing cells (Brennan et al., 2000; Roskoski, 2014). <ref>DOI 10.1016/j.ccell.2018.09.010</ref>
[[Image:Dg_sb_Figure2.jpg|frame|center|Extracellular module structures for the EGFR family members
[[Image:Dg_sb_Figure2.jpg|frame|center|Extracellular module structures for the EGFR family members
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A) The conformational change induced by ligand binding. The tethered conformation of EGFR (left, PDB ID 1NQL, EGF bound at low pH was removed for clarity) rearranges to the extended conformation of EGFR (right, PDB ID 3NJP) upon ligand binding. B) Unliganded Her3 (PDB ID 1M6B) and Her4 (PDB ID 2AHX) can adopt a tethered conformation similar to EGFR, while Her2 (PDB ID 1N8H) is in an extended conformation, even in the absence of ligand.]]
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A) The conformational change induced by ligand binding. The tethered conformation of EGFR (left, PDB ID 1NQL, EGF bound at low pH was removed for clarity) rearranges to the extended conformation of EGFR (right, PDB ID 3NJP) upon ligand binding. B) Unliganded Her3 (PDB ID 1M6B) and Her4 (PDB ID 2AHX) can adopt a tethered conformation similar to EGFR, while Her2 (PDB ID 1N8H) is in an extended conformation, even in the absence of ligand.<ref>DOI 10.1146/annurev-biochem-060614-034402</ref>]]

Revision as of 20:47, 27 April 2022

ErbB2

Caption for this structure

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References

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  23. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010
  24. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010
  25. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010
  26. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010
  27. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010
  28. Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub, 2018 Oct 25. PMID:30449325 doi:http://dx.doi.org/10.1016/j.ccell.2018.09.010

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