ArticleJournal of molecular biology2007
The role of L1 loop in the mechanism of rhomboid intramembrane protease GlpG.
Article in Journal of molecular biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 78 citations in OpenAlex.
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- Steric trapping strategy for studying the folding of helical membrane proteins.Methods (San Diego, Calif.) · 2024Review
- The opening dynamics of the lateral gate regulates the activity of rhomboid proteases.Science advances · 2023Article
- Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates.Cell reports · 2021Article
- A combination of solid-state NMR and MD simulations reveals the binding mode of a rhomboid protease inhibitor.Chemical science · 2021Article
- The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release.Cellular and molecular life sciences : CMLS · 2021Article
- Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease.The Journal of membrane biology · 2020Review
- Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Membrane cholesterol as regulator of human rhomboid protease RHBDL4.The Journal of biological chemistry · 2018Article
- Single amino acid mutation of SR-BI decreases infectivity of hepatitis C virus derived from cell culture in a cell culture model.World journal of gastroenterology · 2017Article
- Regulation of KCNQ/Kv7 family voltage-gated KBiochimica et biophysica acta. Biomembranes · 2017Review
- Steric trapping reveals a cooperativity network in the intramembrane protease GlpG.Nature chemical biology · 2016Article
- Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.The Journal of membrane biology · 2015Review
- Influence of hydrophobic mismatch on the catalytic activity of Escherichia coli GlpG rhomboid protease.Protein science : a publication of the Protein Society · 2015Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
- Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures.The EMBO journal · 2014Article
- Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.Structure (London, England : 1993) · 2014Article
- Biochemical and structural insights into intramembrane metalloprotease mechanisms.Biochimica et biophysica acta · 2013Review
- The roles of intramembrane proteases in protozoan parasites.Biochimica et biophysica acta · 2013Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
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 the L1 loop is partially embedded in the membrane, and showed that alanine substitution of a highly preferred tryptophan (Trp136) at the distal tip of the L1 loop near the 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 A resolution, also clearly defined a 20-A-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 the substrate transmembrane helix first partitions out of the hydrophobic core region of the membrane before it bends into the protease active site for cleavage.
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