Structural comparison of substrate entry gate for rhomboid intramembrane peptidases

• Published in: Biochemistry and cell biology Vol. 89; no. 2; pp. 216 - 223
• Main Authors: Lazareno-Saez, Christelle, Brooks, Cory L, Lemieux, M Joanne
• Format: Journal Article
• Language: English
• Published: Canada NRC Research Press 01.04.2011; Canadian Science Publishing NRC Research Press
• Subjects: Amino Acid Sequence; Binding Sites; Biochemistry; E coli; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - metabolism; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membranes; Models, Molecular; Molecular biology; Molecular Sequence Data; Molecular structure; Molecules; Peptide Hydrolases - chemistry; Peptide Hydrolases - metabolism; Proteases; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Signal transduction; Structure; Studies; Substrate Specificity; Substrates; Canada
• ISSN: 0829-8211; 1208-6002
• DOI: 10.1139/O10-161

Rhomboids are intramembrane serine peptidases conserved in all kingdoms of life. Their general role is to cleave integral membrane proteins to release signalling molecules. These signals, when disrupted, can contribute to various diseases. Crystal structures of H. influenzae (hiGlpG) and E. coli GlpG (ecGlpG) rhomboids have revealed a structure with six transmembrane helices and a Ser-His catalytic dyad buried within the membrane. One emerging issue was the identification of the mobile element in the protein that allows substrate docking. It has been proposed that the substrate entry gate is composed of helix 5 and loop 5. The present review studies the structures of these two orthologs. In ecGlpG structures, different conformations of loop 5 and helix 5 are observed. Open and closed conformations of ecGlpG structures are compared with each other and with hiGlpG, surveying differences in hydrophobic interactions within loop 5 and helix 5. Furthermore, a comparison of the ecGlpG and hiGlpG structures reveals differences in loop 4. Overall, less variation is observed in loop 4, suggesting this region acts as an anchor for the substrate gate. Functional and regulatory implications of these variations are discussed.