2hz6
From Proteopedia
(New page: 200px<br /><applet load="2hz6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hz6, resolution 3.10Å" /> '''The crystal structur...) |
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| - | [[Image:2hz6.gif|left|200px]]<br /><applet load="2hz6" size=" | + | [[Image:2hz6.gif|left|200px]]<br /><applet load="2hz6" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hz6, resolution 3.10Å" /> | caption="2hz6, resolution 3.10Å" /> | ||
'''The crystal structure of human IRE1-alpha luminal domain'''<br /> | '''The crystal structure of human IRE1-alpha luminal domain'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The unfolded protein response (UPR) is an evolutionarily conserved | + | The unfolded protein response (UPR) is an evolutionarily conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type I transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1alpha. The monomer of the luminal domain comprises a unique fold of a triangular assembly of beta-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHC-like groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1alpha molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling. |
==About this Structure== | ==About this Structure== | ||
| - | 2HZ6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 2HZ6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HZ6 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Kaufman, R | + | [[Category: Kaufman, R J.]] |
[[Category: Xu, Z.]] | [[Category: Xu, Z.]] | ||
[[Category: Zhou, J.]] | [[Category: Zhou, J.]] | ||
[[Category: triangular beta-sheet cluster]] | [[Category: triangular beta-sheet cluster]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:47:22 2008'' |
Revision as of 15:47, 21 February 2008
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The crystal structure of human IRE1-alpha luminal domain
Overview
The unfolded protein response (UPR) is an evolutionarily conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type I transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1alpha. The monomer of the luminal domain comprises a unique fold of a triangular assembly of beta-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHC-like groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1alpha molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling.
About this Structure
2HZ6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response., Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ, Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14343-8. Epub 2006 Sep 14. PMID:16973740
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