Structure of a presenilin family intramembrane aspartate protease

@article{Li2013StructureOA,
  title={Structure of a presenilin family intramembrane aspartate protease},
  author={Xiaochun Li and Shangyu Dang and Chuangye Yan and Xinqi Gong and Jiawei Wang and Yigong Shi},
  journal={Nature},
  year={2013},
  volume={493},
  pages={56-61}
}
Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1. The protease, comprising nine transmembrane segments (TMs), adopts a previously unreported protein fold. The amino-terminal… 
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References

SHOWING 1-10 OF 67 REFERENCES
Crystal structure of a rhomboid family intramembrane protease
TLDR
The crystal structure of the GlpG core domain indicates that, in intramembrane proteolysis, the scission of peptide bonds takes place within the hydrophobic environment of the membrane bilayer.
Structure of a Site-2 Protease Family Intramembrane Metalloprotease
TLDR
The crystal structure of the transmembrane core domain of an S2P metalloprotease from Methanocaldococcus jannaschii reveals how zinc embedded in an integral membrane protein can catalyze peptide cleavage.
A C-terminal Region of Signal Peptide Peptidase Defines a Functional Domain for Intramembrane Aspartic Protease Catalysis*
TLDR
Surprisingly, the conserved C-terminal half of SPP is sufficient for proteolytic activity; purification and reconstitution of this engineered fragment of several SPP orthologues revealed that this region defines a functional domain for an intramembrane aspartyl protease.
Identification of an Archaeal Presenilin-Like Intramembrane Protease
TLDR
The findings suggest that a primitive GXGD-type diaspartyl intramembrane protease from archaea can recapitulate key biochemical properties of eukaryotic presenilins and SPPs.
The crystal structure of GXGD membrane protease FlaK
TLDR
The crystal structure of FlaK, a preflagellin peptidase from Methanococcus maripaludis, solved at 3.6 Å resolution, provides a framework for understanding the mechanism of the GXGD proteases, and may facilitate the rational design of inhibitors that target specific members of the family.
Structural analysis of a rhomboid family intramembrane protease reveals a gating mechanism for substrate entry
TLDR
The crystal structure of the transmembrane core domain of GlpG, a rhomboid-family intramembrane serine protease from Escherichia coli, is reported, suggesting that substrate entry to the active site is probably gated by the movement of helix α5.
Three-dimensional structure of the signal peptide peptidase.
TLDR
The structure of human SPP is analyzed by electron microscopy and reconstructed and it is suggested that the homotetramer is the functional unit of SPP and that its N-terminal region has a novel modulatory function for the intramembrane-cleaving activity ofSPP.
Contribution of Presenilin Transmembrane Domains 6 and 7 to a Water-containing Cavity in the γ-Secretase Complex*
TLDR
Experimental evidence for the existence of a water-filled cavity in the catalytic core of Presenilin is provided and it is demonstrated that the two aspartates reside within this cavity and are opposed to each other in the native complex.
Structural basis for intramembrane proteolysis by rhomboid serine proteases
TLDR
The results reveal a mechanism to enable water-dependent catalysis at the depth of the hydrophobic milieu of the membrane and suggest how substrates gain access to the sequestered rhomboid active site.
The crystal structure of the rhomboid peptidase from Haemophilus influenzae provides insight into intramembrane proteolysis
TLDR
The structural results on these rhomboid peptidases have allowed us to speculate on the catalytic mechanism of substrate cleavage in a membranous environment and to identify the relative disposition of the nucleophilic serine to the general base/acid function of the conserved histidine.
...
1
2
3
4
5
...