1. Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
2. Present address: College of Life Science, Jilin University, Changchun 130023, China

Correspondence to: Ya Ha¹ Correspondence and requests for materials should be addressed to Y.H. (Email: ya.ha@yale.edu). The atomic coordinates of GlpG have been deposited in the Protein Data Bank (accession number 2IC8), and will be released upon publication of the paper.

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 -secretase, are unique in that they cleave the transmembrane domain of other membrane proteins. Here we describe the 2.1 Å 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.

1. Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
2. Present address: College of Life Science, Jilin University, Changchun 130023, China

Correspondence to: Ya Ha¹ Correspondence and requests for materials should be addressed to Y.H. (Email: ya.ha@yale.edu). The atomic coordinates of GlpG have been deposited in the Protein Data Bank (accession number 2IC8), and will be released upon publication of the paper.

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