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TMD possesses an amphiphilic quality resulting from a stretch of polar residues along one face of the N-terminus of the TMD helix (S649, T652, S653, S656. The most frequent mutations identified in patient data set (V659E and G660D/R) extend this polar strip. This observation implies the polar character of these mutations amplifies intrinsic properties of the native TMD which may be an essential feature leading to the activating effect of these mutations on HER2.
TMD possesses an amphiphilic quality resulting from a stretch of polar residues along one face of the N-terminus of the TMD helix (S649, T652, S653, S656. The most frequent mutations identified in patient data set (V659E and G660D/R) extend this polar strip. This observation implies the polar character of these mutations amplifies intrinsic properties of the native TMD which may be an essential feature leading to the activating effect of these mutations on HER2.
[[Image:Dg_sb_Figure3.png|frame|center|HER2 mutations in patient tumors.
[[Image:Dg_sb_Figure3.png|frame|center|HER2 mutations in patient tumors.
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Amino acid composition of the TMD in WT HER2 (PDB ID: 2JWA) and in V659E, G660D, or G660R mutants, highlighting the relative arrangement of side chain atoms of polar (oxygen (red) and nitrogen (blue) atoms shown as spheres) and apolar (carbon atoms (green) shown as sticks) residues.]]
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Amino acid composition of the TMD in WT HER2 (PDB ID: 2JWA) and in V659E, G660D, or G660R mutants, highlighting the relative arrangement of side chain atoms of polar (oxygen (red) and nitrogen (blue) atoms shown as spheres) and apolar (carbon atoms (green) shown as sticks) <ref>residues.doi:10.1016/j.ccell.2018.09.010</ref>]]
Proper positioning of the S656-xxx-G660 motif for productive TMD dimer formation is highly dependent on the orientation and geometry of the monomeric TMD helices, defined by basic residues near the interfacial regions between the cytoplasm and head group region of the bilayer (Gleason et al., 2013; Hristova and Wimley, 2011; Kim et al., 2011). Activating HER2 mutations such as R678Q might have a significant effect on the TMD geometry and dimerization. This was tested by performing all-atom 100 ns MD simulations for wild-type (WT) and the WT/R678Q HER2 TMD dimers in a phospholipid bilayer. The coordinates of the HER2 TM dimer in the putative activated conformation determined by NMR (PDB ID: 2JWA) were used as the starting positions in the simulations. The conformation of the WT HER2 TMD homodimer (WT/WT) remains stable over the course of the simulation. In the WT/R678Q TMD heterodimer, the S656-xxx-G660 motif remained engaged for the duration of the simulation, albeit through different interactions. However, the R678Q containing region of the C-termini separated by several angstroms compared to the WT homodimer (Figure 4). Despite these differences, in both WT/WT and WT/R678Q dimers, the conformations observed in the final state are consistent with a geometry proposed to support an activated, asymmetric configuration of the cytoplasmic kinase domains, and suggests that the enhanced activity of the mutant may be the result of its stabilizing effect on the specific heterodimeric configuration required for signaling.
Proper positioning of the S656-xxx-G660 motif for productive TMD dimer formation is highly dependent on the orientation and geometry of the monomeric TMD helices, defined by basic residues near the interfacial regions between the cytoplasm and head group region of the bilayer (Gleason et al., 2013; Hristova and Wimley, 2011; Kim et al., 2011). Activating HER2 mutations such as R678Q might have a significant effect on the TMD geometry and dimerization. This was tested by performing all-atom 100 ns MD simulations for wild-type (WT) and the WT/R678Q HER2 TMD dimers in a phospholipid bilayer. The coordinates of the HER2 TM dimer in the putative activated conformation determined by NMR (PDB ID: 2JWA) were used as the starting positions in the simulations. The conformation of the WT HER2 TMD homodimer (WT/WT) remains stable over the course of the simulation. In the WT/R678Q TMD heterodimer, the S656-xxx-G660 motif remained engaged for the duration of the simulation, albeit through different interactions. However, the R678Q containing region of the C-termini separated by several angstroms compared to the WT homodimer (Figure 4). Despite these differences, in both WT/WT and WT/R678Q dimers, the conformations observed in the final state are consistent with a geometry proposed to support an activated, asymmetric configuration of the cytoplasmic kinase domains, and suggests that the enhanced activity of the mutant may be the result of its stabilizing effect on the specific heterodimeric configuration required for signaling.

Revision as of 20:38, 27 April 2022

ErbB2

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References

  1. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997 Apr 1;16(7):1647-55. doi: 10.1093/emboj/16.7.1647. PMID:9130710 doi:http://dx.doi.org/10.1093/emboj/16.7.1647
  2. Wada T, Qian XL, Greene MI. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990 Jun 29;61(7):1339-47. doi: 10.1016/0092-8674(90)90697-d. PMID:1973074 doi:http://dx.doi.org/10.1016/0092-8674(90)90697-d
  3. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006 Jul;7(7):505-16. doi: 10.1038/nrm1962. PMID:16829981 doi:http://dx.doi.org/10.1038/nrm1962
  4. Slamon DJ, Clark GM. Amplification of c-erbB-2 and aggressive human breast tumors? Science. 1988 Jun 24;240(4860):1795-8. doi: 10.1126/science.3289120. PMID:3289120 doi:http://dx.doi.org/10.1126/science.3289120
  5. Venter DJ, Tuzi NL, Kumar S, Gullick WJ. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification. Lancet. 1987 Jul 11;2(8550):69-72. doi: 10.1016/s0140-6736(87)92736-x. PMID:2885574 doi:http://dx.doi.org/10.1016/s0140-6736(87)92736-x
  6. Fleishman SJ, Schlessinger J, Ben-Tal N. A putative molecular-activation switch in the transmembrane domain of erbB2. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15937-40. doi:, 10.1073/pnas.252640799. Epub 2002 Dec 2. PMID:12461170 doi:http://dx.doi.org/10.1073/pnas.252640799
  7. Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14476-81. doi:, 10.1073/pnas.1203201109. Epub 2012 Aug 20. PMID:22908275 doi:http://dx.doi.org/10.1073/pnas.1203201109
  8. Zabransky DJ, Yankaskas CL, Cochran RL, Wong HY, Croessmann S, Chu D, Kavuri SM, Red Brewer M, Rosen DM, Dalton WB, Cimino-Mathews A, Cravero K, Button B, Kyker-Snowman K, Cidado J, Erlanger B, Parsons HA, Manto KM, Bose R, Lauring J, Arteaga CL, Konstantopoulos K, Park BH. HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):E6205-14. doi:, 10.1073/pnas.1516853112. Epub 2015 Oct 27. PMID:26508629 doi:http://dx.doi.org/10.1073/pnas.1516853112
  9. Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, Bose R, Vergilio JA, Suh J, Yelensky R, Lipson D, Chmielecki J, Waintraub S, Leyland-Jones B, Miller VA, Stephens PJ. Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. Cancer. 2016 Sep 1;122(17):2654-62. doi: 10.1002/cncr.30102. Epub 2016 Jun 10. PMID:27284958 doi:http://dx.doi.org/10.1002/cncr.30102
  10. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S, Ma CX, Ding L, Mardis ER, Ellis MJ. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013 Feb;3(2):224-37. doi: 10.1158/2159-8290.CD-12-0349. Epub 2012, Dec 7. PMID:23220880 doi:http://dx.doi.org/10.1158/2159-8290.CD-12-0349
  11. Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, Furukawa M, Hashida S, Tsukuda K, Takigawa N, Matsuo K, Kiura K, Miyoshi S, Matsuda F, Toyooka S. Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst. 2014 Jan;106(1):djt338. doi: 10.1093/jnci/djt338. Epub 2013, Dec 7. PMID:24317180 doi:http://dx.doi.org/10.1093/jnci/djt338
  12. Kavuri SM, Jain N, Galimi F, Cottino F, Leto SM, Migliardi G, Searleman AC, Shen W, Monsey J, Trusolino L, Jacobs SA, Bertotti A, Bose R. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015 Aug;5(8):832-41. doi: 10.1158/2159-8290.CD-14-1211. PMID:26243863 doi:http://dx.doi.org/10.1158/2159-8290.CD-14-1211
  13. Ou SI, Schrock AB, Bocharov EV, Klempner SJ, Haddad CK, Steinecker G, Johnson M, Gitlitz BJ, Chung J, Campregher PV, Ross JS, Stephens PJ, Miller VA, Suh JH, Ali SM, Velcheti V. HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib. J Thorac Oncol. 2017 Mar;12(3):446-457. doi: 10.1016/j.jtho.2016.11.2224. Epub, 2016 Nov 27. PMID:27903463 doi:http://dx.doi.org/10.1016/j.jtho.2016.11.2224
  14. Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, Chakravarty D, Phillips S, Kandoth C, Penson A, Gorelick A, Shamu T, Patel S, Harris C, Gao J, Sumer SO, Kundra R, Razavi P, Li BT, Reales DN, Socci ND, Jayakumaran G, Zehir A, Benayed R, Arcila ME, Chandarlapaty S, Ladanyi M, Schultz N, Baselga J, Berger MF, Rosen N, Solit DB, Hyman DM, Taylor BS. Accelerating Discovery of Functional Mutant Alleles in Cancer. Cancer Discov. 2018 Feb;8(2):174-183. doi: 10.1158/2159-8290.CD-17-0321. Epub, 2017 Dec 15. PMID:29247016 doi:http://dx.doi.org/10.1158/2159-8290.CD-17-0321
  15. Petrelli F, Tomasello G, Barni S, Lonati V, Passalacqua R, Ghidini M. Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature. Breast Cancer Res Treat. 2017 Nov;166(2):339-349. doi: 10.1007/s10549-017-4419-x., Epub 2017 Jul 31. PMID:28762010 doi:http://dx.doi.org/10.1007/s10549-017-4419-x
  16. Cousin S, Khalifa E, Crombe A, Laizet Y, Lucchesi C, Toulmonde M, Le Moulec S, Auzanneau C, Soubeyran I, Italiano A. Targeting ERBB2 mutations in solid tumors: biological and clinical implications. J Hematol Oncol. 2018 Jun 25;11(1):86. doi: 10.1186/s13045-018-0630-4. PMID:29941010 doi:http://dx.doi.org/10.1186/s13045-018-0630-4
  17. residues.doi:10.1016/j.ccell.2018.09.010

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