NDLI: The role of L1 loop in the mechanism of rhomboid intramembrane protease GlpG

Content Provider	PubMed Central
Author	Wang, Yongcheng Maegawa, Saki Akiyama, Yoshinori Ha, Ya
Abstract	Intramembrane proteases are important enzymes in biology. The recently solved crystal structures of rhomboid protease GlpG have provided useful insights into the mechanism of these membrane proteins. Besides revealing an internal water-filled cavity that harbored the Ser-His catalytic dyad, the crystal structure identified a novel structural domain (L1 loop) that lies on the side of the transmembrane helices. Here using site-directed mutagenesis we confirmed that L1 loop is partially embedded in the membrane, and showed that alanine substitution of a highly preferred tryptophan (Trp-136) at the distal tip of L1 loop near lipid:water interface reduced GlpG proteolytic activity. Crystallographic analysis showed that W136A mutation did not modify the structure of the protease. Instead, the polarity for a small and lipid-exposed protein surface, at the site of the mutation, has changed. The crystal structure, now refined at 1.7 Å resolution, also clearly defined a 20 Å wide hydrophobic belt around the protease, which likely corresponded to the thickness of the compressed membrane bilayer around the protein. This improved structural model predicts that all critical elements of the catalysis, including the catalytic serine and the L5 cap, need to be positioned within a few angstroms of the membrane surface, and may explain why the protease activity is sensitive to changes in the protein:lipid interaction. Based on these findings, we propose a model where the end of substrate transmembrane helix first partitions out of the hydrophobic core region of the membrane before it bends into the protease active site for cleavage.
Related Links	http://dx.doi.org/10.1016/j.jmb.2007.10.014
Ending Page	1113
Page Count	10
Starting Page	1104
File Format	PDF
ISSN	00222836
e-ISSN	10898638
Journal	Journal of molecular biology
Issue Number	4
Volume Number	374
Language	English
Publisher Date	2007-12-01
Access Restriction	Open
Subject Keyword	Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Structural Biology Molecular Biology Biophysics

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