BIOCHEMISTRY: Through the Side Door

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Science  04 May 2007:
Vol. 316, Issue 5825, pp. 662d-663d
DOI: 10.1126/science.316.5825.662d

The hydrolysis of peptide bonds is a common-place biochemical reaction and is catalyzed by innumerable proteases and peptidases, most of which have excruciatingly well-documented mechanisms. Because both of the reaction substrates are hydrophilic, it is not surprising that these enzymes are found and do function in aqueous compartments; a handful of proteases are, however, integral membrane proteins. Recent structural descriptions of the bacterial enzyme GlpG have placed the catalytic serine residue at a depth of about 10 Å beneath the surface of the lipid bilayer, which fits with the predicted location of the hydrolyzed peptide bonds in known intramembrane protease substrates.

Baker et al. have mutated carefully chosen residues in GlpG and assessed the ability of the mutants to cleave the Drosophila protein Spitz, which is the substrate of the Drosophila intramembrane protease Rhomboid. They find that the substrate is likely to gain access, not by lifting the lidlike L1 loop on top of the active site, but by entering from within the lipid bilayer via a displacement of transmembrane helix 5, in a manner that is reminiscent of the translocon-mediated expulsion of newly synthesized membrane proteins. — GJC

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.0700814104 (2007).

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