title: Crystal structure of a rhomboid family intramembrane protease.
abstract: Escherichia coli GlpG is an integral membrane protein that belongs to the widespread rhomboid protease family. Rhomboid proteases, like site-2 protease (S2P) and gamma-secretase, are unique in that they cleave the transmembrane domain of other membrane proteins. Here we describe the 2.1 A resolution crystal structure of the GlpG core domain. This structure contains six transmembrane segments. Residues previously shown to be involved in catalysis, including a Ser-His dyad, and several water molecules are found at the protein interior at a depth below the membrane surface. This putative active site is accessible by substrate through a large 'V-shaped' opening that faces laterally towards the lipid, but is blocked by a half-submerged loop structure. These observations indicate that, in intramembrane proteolysis, the scission of peptide bonds takes place within the hydrophobic environment of the membrane bilayer. The crystal structure also suggests a gating mechanism for GlpG that controls substrate access to its hydrophilic active site.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Yingjiu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ya
authors.initials: Y
authors.lastname: Ha
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D002384:Catalysis; D002462:Cell Membrane / Q000201:enzymology*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000145:classification* / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry* / Q000145:classification* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000145:classification* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000145:classification* / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C102898:GlpG protein, E coli; D008565:Membrane Proteins; D014867:Water; D010450:Endopeptidases