Journal:MicroPubl Biol:000763
From Proteopedia
(Difference between revisions)
| Line 4: | Line 4: | ||
<hr/> | <hr/> | ||
<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | IRE1, a sensor protein found in the endoplasmic reticulum (ER) of eukaryotic cells. IRE1 is involved in the Unfolded Protein Response (UPR), a cellular stress response pathway that helps cells cope with the stress caused by the accumulation of unfolded proteins in the ER. Structurally IRE1 has a sensory N-terminal domain towards the ER lumen, a C-terminal catalytic domain towards the cytosol, and a linker region connecting the two domains. The activation of IRE1 requires dimerization/oligomerization in the lumenal domain, which functionally activates the catalytic C-terminal domain. The quaternary structure of IRE1 lumenal dimer was deduced from the crystal structure published earlier, which suggested that a large stable interface is formed through a beta-sheet spreading across the dimer subunits. However, there are two problems with this form of the quaternary structure. First, the presence of a strong interface implies that a large activation and deactivation energy may be needed to alter the monomer-dimer equilibrium, which may not be adequate for a sensor protein. Second, the end-to-end distance of the C-termini of the lumenal domain between two monomers is 62.8 Å, which requires a cytoplasmic domain with same distance. However, this structure does not fit well with experimental data. | + | IRE1, a sensor protein found in the endoplasmic reticulum (ER) of eukaryotic cells. IRE1 is involved in the Unfolded Protein Response (UPR), a cellular stress response pathway that helps cells cope with the stress caused by the accumulation of unfolded proteins in the ER. Structurally IRE1 has a sensory N-terminal domain towards the ER lumen, a C-terminal catalytic domain towards the cytosol, and a linker region connecting the two domains. The activation of IRE1 requires dimerization/oligomerization in the lumenal domain, which functionally activates the catalytic C-terminal domain. The quaternary structure of IRE1 lumenal dimer was deduced from the crystal structure published earlier, which suggested that a large stable interface is formed through a beta-sheet spreading across the dimer subunits. However, there are two problems with this form of the quaternary structure. First, the presence of a strong interface implies that a large activation and deactivation energy may be needed to alter the monomer-dimer equilibrium, which may not be adequate for a sensor protein. Second, the end-to-end distance of the C-termini of the lumenal domain between two monomers is 62.8 Å, which requires a cytoplasmic domain with same distance. However, this structure does not fit well with experimental data. <scene name='95/956393/Cv/3'>TextToBeDisplayed</scene> |
To address these issues, we present an alternative quaternary structural model for dimerization of IRE1 lumenal domain. In this model, the lumenal domain dimer has a side-by-side orientation, which is less stable than the previous model and has a shorter distance of 42.8 Å. A corresponding C-terminal domain that matches it, has a N-terminal separation of 41.7 Å, which has been suggested to be the correct dimerization state of the IRE1 C-terminal domain. In our model, the dimer form of the luminal domain is less stable with an interface area of 1130 Å and theoretical interaction and dissociation free energy values of -12.3 and 0.3 kcal/mol, respectively. On the other hand, other quaternary structure of IRE1 is more stable, with an interface area of 1730 Å and theoretical interaction and dissociation free energy values of -15.2 and 7.2 kcal/mol, respectively. The dimer form, however, still has a reasonably large interface area and low dissociation free energy, which means it can easily switch between a monomer and dimer state. Additionally, the luminal-C-terminal domain separation of approximately 40 Å is more likely to stabilize the full IRE1 protein in its functional form. | To address these issues, we present an alternative quaternary structural model for dimerization of IRE1 lumenal domain. In this model, the lumenal domain dimer has a side-by-side orientation, which is less stable than the previous model and has a shorter distance of 42.8 Å. A corresponding C-terminal domain that matches it, has a N-terminal separation of 41.7 Å, which has been suggested to be the correct dimerization state of the IRE1 C-terminal domain. In our model, the dimer form of the luminal domain is less stable with an interface area of 1130 Å and theoretical interaction and dissociation free energy values of -12.3 and 0.3 kcal/mol, respectively. On the other hand, other quaternary structure of IRE1 is more stable, with an interface area of 1730 Å and theoretical interaction and dissociation free energy values of -15.2 and 7.2 kcal/mol, respectively. The dimer form, however, still has a reasonably large interface area and low dissociation free energy, which means it can easily switch between a monomer and dimer state. Additionally, the luminal-C-terminal domain separation of approximately 40 Å is more likely to stabilize the full IRE1 protein in its functional form. | ||
Revision as of 14:23, 12 March 2023
| |||||||||||
This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
