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Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.

Arkhipov A, Shan Y, Kim ET, Dror RO, Shaw DE - Elife (2013)

Bottom Line: The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation.The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric.This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human.

View Article: PubMed Central - PubMed

Affiliation: D. E. Shaw Research , New York , United States.

ABSTRACT
The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOI:http://dx.doi.org/10.7554/eLife.00708.001.

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Her3–Her2 heterodimer.(A) Snapshots from the simulations of the Her3–Her2 heterodimer with (left) and without (right) HRG bound to Her3. At the end of the simulation with HRG bound to Her3, HRG was removed, and the resulting system was resolvated and further simulated without the ligand. A gap opened in the dimer interface, as illustrated by the snapshot on the right. For clarity, these images omit domain IV. (B) The surface area buried within the dimer interface, counting the contributions only from domains I, II, and III, plotted as a function of time. Two independent sets of two simulations each (with and without HRG) are shown.DOI:http://dx.doi.org/10.7554/eLife.00708.008
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fig5: Her3–Her2 heterodimer.(A) Snapshots from the simulations of the Her3–Her2 heterodimer with (left) and without (right) HRG bound to Her3. At the end of the simulation with HRG bound to Her3, HRG was removed, and the resulting system was resolvated and further simulated without the ligand. A gap opened in the dimer interface, as illustrated by the snapshot on the right. For clarity, these images omit domain IV. (B) The surface area buried within the dimer interface, counting the contributions only from domains I, II, and III, plotted as a function of time. Two independent sets of two simulations each (with and without HRG) are shown.DOI:http://dx.doi.org/10.7554/eLife.00708.008

Mentions: The resulting model of the Her3–Her2 heterodimer was then simulated, first with HRG bound, in which case the dimer interface remained stable (Figure 5A). After ∼4 µs of simulation the ligand was removed, and the resulting ligand-free heterodimer was then simulated again. Without the ligand, the Her3 subunit underwent conformational changes similar to those described above for the ligand-free EGFR subunit, including a bending of domain II. As a result, a gap again emerged in the dimer interface. In the first series of simulations the gap in the Her3–Her2 heterodimer was often partially closed, but re-opened repeatedly and resulted in a significant decrease in the buried surface area in the dimer interface. In the second series, the gap was steadily open once the ligand was removed (Figure 5B). These observations suggest that Her3–Her2 heterodimerization, similar to that of EGFR–Her2, is promoted by the stabilization of the dimer interface following ligand binding.10.7554/eLife.00708.008Figure 5.Her3–Her2 heterodimer.


Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.

Arkhipov A, Shan Y, Kim ET, Dror RO, Shaw DE - Elife (2013)

Her3–Her2 heterodimer.(A) Snapshots from the simulations of the Her3–Her2 heterodimer with (left) and without (right) HRG bound to Her3. At the end of the simulation with HRG bound to Her3, HRG was removed, and the resulting system was resolvated and further simulated without the ligand. A gap opened in the dimer interface, as illustrated by the snapshot on the right. For clarity, these images omit domain IV. (B) The surface area buried within the dimer interface, counting the contributions only from domains I, II, and III, plotted as a function of time. Two independent sets of two simulations each (with and without HRG) are shown.DOI:http://dx.doi.org/10.7554/eLife.00708.008
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713454&req=5

fig5: Her3–Her2 heterodimer.(A) Snapshots from the simulations of the Her3–Her2 heterodimer with (left) and without (right) HRG bound to Her3. At the end of the simulation with HRG bound to Her3, HRG was removed, and the resulting system was resolvated and further simulated without the ligand. A gap opened in the dimer interface, as illustrated by the snapshot on the right. For clarity, these images omit domain IV. (B) The surface area buried within the dimer interface, counting the contributions only from domains I, II, and III, plotted as a function of time. Two independent sets of two simulations each (with and without HRG) are shown.DOI:http://dx.doi.org/10.7554/eLife.00708.008
Mentions: The resulting model of the Her3–Her2 heterodimer was then simulated, first with HRG bound, in which case the dimer interface remained stable (Figure 5A). After ∼4 µs of simulation the ligand was removed, and the resulting ligand-free heterodimer was then simulated again. Without the ligand, the Her3 subunit underwent conformational changes similar to those described above for the ligand-free EGFR subunit, including a bending of domain II. As a result, a gap again emerged in the dimer interface. In the first series of simulations the gap in the Her3–Her2 heterodimer was often partially closed, but re-opened repeatedly and resulted in a significant decrease in the buried surface area in the dimer interface. In the second series, the gap was steadily open once the ligand was removed (Figure 5B). These observations suggest that Her3–Her2 heterodimerization, similar to that of EGFR–Her2, is promoted by the stabilization of the dimer interface following ligand binding.10.7554/eLife.00708.008Figure 5.Her3–Her2 heterodimer.

Bottom Line: The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation.The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric.This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human.

View Article: PubMed Central - PubMed

Affiliation: D. E. Shaw Research , New York , United States.

ABSTRACT
The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOI:http://dx.doi.org/10.7554/eLife.00708.001.

Show MeSH
Related in: MedlinePlus