A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

Huang, Yongjian; Ognjenovic, Jana; Karandur, Deepti; Miller, Kate; Merk, Alan; Subramaniam, Sriram; Kuriyan, John

doi:10.7554/elife.73218

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

Journal Article · Tue Nov 30 00:00:00 EST 2021 · eLife

DOI:https://doi.org/10.7554/elife.73218· OSTI ID:2470652

^[1]; Ognjenovic, Jana ^[2]; ^[1]; Miller, Kate ^[1]; Merk, Alan ^[2]; ^[3]; ^[4]

University of California, Berkeley, CA (United States)
Frederick National Lab. for Cancer Research, Frederick, MD (United States)
Univ. of British Columbia, Vancouver, BC (Canada)
University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470652

Journal Information:: eLife, Journal Name: eLife Vol. 10; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

References (74)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
CHARMM-GUI: A web-based graphical user interface for CHARMM Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G. Journal of Computational Chemistry, Vol. 29, Issue 11 https://doi.org/10.1002/jcc.20945	journal	March 2008
CHARMM-GUI Membrane Builder toward realistic biological membrane simulations Wu, Emilia L.; Cheng, Xi; Jo, Sunhwan Journal of Computational Chemistry, Vol. 35, Issue 27 https://doi.org/10.1002/jcc.23702	journal	August 2014
THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130812	journal	October 1992
A New Generation of the IMAGIC Image Processing System van Heel, Marin; Harauz, George; Orlova, Elena V. Journal of Structural Biology, Vol. 116, Issue 1 https://doi.org/10.1006/jsbi.1996.0004	journal	January 1996
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling Torrie, G. M.; Valleau, J. P. Journal of Computational Physics, Vol. 23, Issue 2 https://doi.org/10.1016/0021-9991(77)90121-8	journal	February 1977
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Reconstitution of Membrane Proteins in Phospholipid Bilayer Nanodiscs Ritchie, T. K.; Grinkova, Y. V.; Bayburt, T. H. Methods in Enzymology https://doi.org/10.1016/S0076-6879(09)64011-8	book	January 2009
Alternative packing of EGFR transmembrane domain suggests that protein–lipid interactions underlie signal conduction across membrane Bocharov, Eduard V.; Lesovoy, Dmitry M.; Pavlov, Konstantin V. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 6 https://doi.org/10.1016/j.bbamem.2016.02.023	journal	June 2016
Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations Pahuja, Kanika Bajaj; Nguyen, Thong T.; Jaiswal, Bijay S. Cancer Cell, Vol. 34, Issue 5 https://doi.org/10.1016/j.ccell.2018.09.010	journal	November 2018
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics Arteaga, Carlos L.; Engelman, Jeffrey A. Cancer Cell, Vol. 25, Issue 3 https://doi.org/10.1016/j.ccr.2014.02.025	journal	March 2014
An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor Zhang, Xuewu; Gureasko, Jodi; Shen, Kui Cell, Vol. 125, Issue 6 https://doi.org/10.1016/j.cell.2006.05.013	journal	June 2006
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment Jura, Natalia; Endres, Nicholas F.; Engel, Kate Cell, Vol. 137, Issue 7 https://doi.org/10.1016/j.cell.2009.04.025	journal	June 2009
Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization Shan, Yibing; Eastwood, Michael P.; Zhang, Xuewu Cell, Vol. 149, Issue 4 https://doi.org/10.1016/j.cell.2012.02.063	journal	May 2012
Architecture and Membrane Interactions of the EGF Receptor Arkhipov, Anton; Shan, Yibing; Das, Rahul Cell, Vol. 152, Issue 3 https://doi.org/10.1016/j.cell.2012.12.030	journal	January 2013
Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor Endres, Nicholas F.; Das, Rahul; Smith, Adam W. Cell, Vol. 152, Issue 3 https://doi.org/10.1016/j.cell.2012.12.032	journal	January 2013
EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics Freed, Daniel M.; Bessman, Nicholas J.; Kiyatkin, Anatoly Cell, Vol. 171, Issue 3 https://doi.org/10.1016/j.cell.2017.09.017	journal	October 2017
Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region Doerner, Amy; Scheck, Rebecca; Schepartz, Alanna Chemistry & Biology, Vol. 22, Issue 6 https://doi.org/10.1016/j.chembiol.2015.05.008	journal	June 2015
Mechanism of Allosteric Coupling into and through the Plasma Membrane by EGFR Sinclair, Julie K. L.; Walker, Allison S.; Doerner, Amy E. Cell Chemical Biology, Vol. 25, Issue 7 https://doi.org/10.1016/j.chembiol.2018.04.005	journal	July 2018
Membrane protein assembly into Nanodiscs Bayburt, Timothy H.; Sligar, Stephen G. FEBS Letters, Vol. 584, Issue 9 https://doi.org/10.1016/j.febslet.2009.10.024	journal	October 2009
Topology representing network enables highly accurate classification of protein images taken by cryo electron-microscope without masking Ogura, Toshihiko; Iwasaki, Kenji; Sato, Chikara Journal of Structural Biology, Vol. 143, Issue 3 https://doi.org/10.1016/j.jsb.2003.08.005	journal	September 2003
Automated molecular microscopy: The new Leginon system Suloway, Christian; Pulokas, James; Fellmann, Denis Journal of Structural Biology, Vol. 151, Issue 1 https://doi.org/10.1016/j.jsb.2005.03.010	journal	July 2005
Appion: An integrated, database-driven pipeline to facilitate EM image processing Lander, Gabriel C.; Stagg, Scott M.; Voss, Neil R. Journal of Structural Biology, Vol. 166, Issue 1 https://doi.org/10.1016/j.jsb.2009.01.002	journal	April 2009
DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy Voss, N. R.; Yoshioka, C. K.; Radermacher, M. Journal of Structural Biology, Vol. 166, Issue 2 https://doi.org/10.1016/j.jsb.2009.01.004	journal	May 2009
Functional selectivity of EGF family peptide growth factors: Implications for cancer Wilson, Kristy J.; Gilmore, Jennifer L.; Foley, John Pharmacology & Therapeutics, Vol. 122, Issue 1 https://doi.org/10.1016/j.pharmthera.2008.11.008	journal	April 2009
Peptides in lipid bilayers: the power of simple models Killian, J. Antoinette; Nyholm, Thomas KM Current Opinion in Structural Biology, Vol. 16, Issue 4 https://doi.org/10.1016/j.sbi.2006.06.007	journal	August 2006
Visualization of Ligand-Bound Ectodomain Assembly in the Full-Length Human IGF-1 Receptor by Cryo-EM Single-Particle Analysis Zhang, Xi; Yu, Daqi; Sun, Jingchuan Structure, Vol. 28, Issue 5 https://doi.org/10.1016/j.str.2020.03.007	journal	May 2020
ACE: Automated CTF Estimation Mallick, Satya P.; Carragher, Bridget; Potter, Clinton S. Ultramicroscopy, Vol. 104, Issue 1 https://doi.org/10.1016/j.ultramic.2005.02.004	journal	August 2005
Binding specificities and affinities of egf domains for ErbB receptors Jones, Jennifer T.; Akita, Robert W.; Sliwkowski, Mark X. FEBS Letters, Vol. 447, Issue 2-3 https://doi.org/10.1016/s0014-5793(99)00283-5	journal	March 1999
Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor α Garrett, Thomas P. J.; McKern, Neil M.; Lou, Meizhen Cell, Vol. 110, Issue 6 https://doi.org/10.1016/s0092-8674(02)00940-6	journal	September 2002
Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains Ogiso, Hideo; Ishitani, Ryuichiro; Nureki, Osamu Cell, Vol. 110, Issue 6 https://doi.org/10.1016/s0092-8674(02)00963-7	journal	September 2002
Accurate determination of local defocus and specimen tilt in electron microscopy Mindell, Joseph A.; Grigorieff, Nikolaus Journal of Structural Biology, Vol. 142, Issue 3 https://doi.org/10.1016/s1047-8477(03)00069-8	journal	June 2003
The Conformation of the Epidermal Growth Factor Receptor Transmembrane Domain Dimer Dynamically Adapts to the Local Membrane Environment Bocharov, Eduard V.; Bragin, Pavel E.; Pavlov, Konstantin V. Biochemistry, Vol. 56, Issue 12 https://doi.org/10.1021/acs.biochem.6b01085	journal	March 2017
In Vitro Enzymatic Characterization of Near Full Length EGFR in Activated and Inhibited States Qiu, Chen; Tarrant, Mary K.; Boronina, Tatiana Biochemistry, Vol. 48, Issue 28 https://doi.org/10.1021/bi900755n	journal	July 2009
Bipartite Tetracysteine Display Reveals Allosteric Control of Ligand-Specific EGFR Activation Scheck, Rebecca A.; Lowder, Melissa A.; Appelbaum, Jacob S. ACS Chemical Biology, Vol. 7, Issue 8 https://doi.org/10.1021/cb300216f	journal	June 2012
Structural Differences between Wild-Type and Double Mutant EGFR Modulated by Third-Generation Kinase Inhibitors Lowder, Melissa A.; Doerner, Amy E.; Schepartz, Alanna Journal of the American Chemical Society, Vol. 137, Issue 20 https://doi.org/10.1021/jacs.5b02326	journal	May 2015
Well-Defined Nanoparticles Formed by Hydrophobic Assembly of a Short and Polydisperse Random Terpolymer, Amphipol A8-35 Gohon, Yann; Giusti, Fabrice; Prata, Carla Langmuir, Vol. 22, Issue 3 https://doi.org/10.1021/la052243g	journal	January 2006
The quest to overcome resistance to EGFR-targeted therapies in cancer Chong, Curtis R.; Jänne, Pasi A. Nature Medicine, Vol. 19, Issue 11 https://doi.org/10.1038/nm.3388	journal	November 2013
CHARMM36m: an improved force field for folded and intrinsically disordered proteins Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4067	journal	November 2016
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4193	journal	February 2017
Image processing for electron microscopy single-particle analysis using XMIPP Scheres, Sjors H. W.; Núñez-Ramírez, Rafael; Sorzano, Carlos O. S. Nature Protocols, Vol. 3, Issue 6 https://doi.org/10.1038/nprot.2008.62	journal	May 2008
Screening and large-scale expression of membrane proteins in mammalian cells for structural studies Goehring, April; Lee, Chia-Hsueh; Wang, Kevin H. Nature Protocols, Vol. 9, Issue 11 https://doi.org/10.1038/nprot.2014.173	journal	October 2014
Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor Mi, Li-Zhi; Lu, Chafen; Li, Zongli Nature Structural & Molecular Biology, Vol. 18, Issue 9 https://doi.org/10.1038/nsmb.2092	journal	August 2011
Structural basis of the activation of type 1 insulin-like growth factor receptor Li, Jie; Choi, Eunhee; Yu, Hongtao Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-12564-0	journal	October 2019
Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface Diwanji, Devan; Trenker, Raphael; Thaker, Tarjani M. Nature, Vol. 600, Issue 7888 https://doi.org/10.1038/s41586-021-04084-z	journal	November 2021
The biophysical basis of receptor tyrosine kinase ligand functional selectivity: Trk-B case study Ahmed, Fozia; Paul, Michael D.; Hristova, Kalina Biochemical Journal, Vol. 477, Issue 23 https://doi.org/10.1042/BCJ20200671	journal	December 2020
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems Darden, Tom; York, Darrin; Pedersen, Lee The Journal of Chemical Physics, Vol. 98, Issue 12 https://doi.org/10.1063/1.464397	journal	June 1993
Constant pressure molecular dynamics algorithms Martyna, Glenn J.; Tobias, Douglas J.; Klein, Michael L. The Journal of Chemical Physics, Vol. 101, Issue 5 https://doi.org/10.1063/1.467468	journal	September 1994
Constant pressure molecular dynamics simulation: The Langevin piston method Feller, Scott E.; Zhang, Yuhong; Pastor, Richard W. The Journal of Chemical Physics, Vol. 103, Issue 11 https://doi.org/10.1063/1.470648	journal	September 1995
A single ligand is sufficient to activate EGFR dimers Liu, P.; Cleveland, T. E.; Bouyain, S. Proceedings of the National Academy of Sciences, Vol. 109, Issue 27 https://doi.org/10.1073/pnas.1201114109	journal	June 2012
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer Red Brewer, M.; Yun, C. -H.; Lai, D. Proceedings of the National Academy of Sciences, Vol. 110, Issue 38 https://doi.org/10.1073/pnas.1220050110	journal	September 2013
Structure and function in rhodopsin: High-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line Reeves, P. J.; Callewaert, N.; Contreras, R. Proceedings of the National Academy of Sciences, Vol. 99, Issue 21 https://doi.org/10.1073/pnas.212519299	journal	October 2002
SHC and GRB-2 Are Constitutively Activated by an Epidermal Growth Factor Receptor with a Point Mutation in the Transmembrane Domain Miloso, Mariarosaria; Mazzotti, Maria; Vass, William C. Journal of Biological Chemistry, Vol. 270, Issue 33 https://doi.org/10.1074/jbc.270.33.19557	journal	August 1995
The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes Mendrola, Jeannine M.; Berger, Mitchell B.; King, Megan C. Journal of Biological Chemistry, Vol. 277, Issue 7 https://doi.org/10.1074/jbc.M108681200	journal	December 2001
Different Epidermal Growth Factor (EGF) Receptor Ligands Show Distinct Kinetics and Biased or Partial Agonism for Homodimer and Heterodimer Formation Macdonald-Obermann, Jennifer L.; Pike, Linda J. Journal of Biological Chemistry, Vol. 289, Issue 38 https://doi.org/10.1074/jbc.M114.586826	journal	September 2014
Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins Ronan, Tom; Macdonald-Obermann, Jennifer L.; Huelsmann, Lorel Journal of Biological Chemistry, Vol. 291, Issue 11 https://doi.org/10.1074/jbc.M115.710087	journal	January 2016
Using collective variables to drive molecular dynamics simulations Fiorin, Giacomo; Klein, Michael L.; Hénin, Jérôme Molecular Physics, Vol. 111, Issue 22-23 https://doi.org/10.1080/00268976.2013.813594	journal	December 2013
The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases Lemmon, M. A.; Schlessinger, J.; Ferguson, K. M. Cold Spring Harbor Perspectives in Biology, Vol. 6, Issue 4 https://doi.org/10.1101/cshperspect.a020768	journal	April 2014
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Real-space refinement in PHENIX for cryo-EM and crystallography Afonine, Pavel V.; Poon, Billy K.; Read, Randy J. Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 6 https://doi.org/10.1107/S2059798318006551	journal	May 2018
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor Lu, Chafen; Mi, Li-Zhi; Grey, Michael J. Molecular and Cellular Biology, Vol. 30, Issue 22 https://doi.org/10.1128/MCB.00742-10	journal	September 2010
Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface Dawson, J. P.; Berger, M. B.; Lin, C. -C. Molecular and Cellular Biology, Vol. 25, Issue 17 https://doi.org/10.1128/MCB.25.17.7734-7742.2005	journal	August 2005
A Structural Perspective on the Regulation of the Epidermal Growth Factor Receptor Kovacs, Erika; Zorn, Julie Anne; Huang, Yongjian Annual Review of Biochemistry, Vol. 84, Issue 1 https://doi.org/10.1146/annurev-biochem-060614-034402	journal	June 2015
EGF receptor ligands: recent advances Singh, Bhuminder; Carpenter, Graham; Coffey, Robert J. F1000Research, Vol. 5 https://doi.org/10.12688/f1000research.9025.1	journal	January 2016
The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells Cai, Wen-Qi; Zeng, Li-Si; Wang, Li-Feng Frontiers in Oncology, Vol. 10 https://doi.org/10.3389/fonc.2020.01249	journal	July 2020
Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab Brand, Toni M.; Iida, Mari; Wheeler, Deric L. Cancer Biology & Therapy, Vol. 11, Issue 9 https://doi.org/10.4161/cbt.11.9.15050	journal	May 2011
The Peptidisc, a simple method for stabilizing membrane proteins in detergent-free solution Carlson, Michael Luke; Young, John William; Zhao, Zhiyu eLife, Vol. 7 https://doi.org/10.7554/eLife.34085	journal	August 2018
New tools for automated high-resolution cryo-EM structure determination in RELION-3 Zivanov, Jasenko; Nakane, Takanori; Forsberg, Björn O. eLife, Vol. 7 https://doi.org/10.7554/eLife.42166	journal	November 2018
Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor–ligand complex Uchikawa, Emiko; Choi, Eunhee; Shang, Guijun eLife, Vol. 8 https://doi.org/10.7554/eLife.48630	journal	August 2019
New approach for membrane protein reconstitution into peptidiscs and basis for their adaptability to different proteins Angiulli, Gabriella; Dhupar, Harveer Singh; Suzuki, Hiroshi eLife, Vol. 9 https://doi.org/10.7554/eLife.53530	journal	March 2020

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