ArticleStructure (London, England : 1993)2012
An internal water-retention site in the rhomboid intramembrane protease GlpG ensures catalytic efficiency.
Article in Structure (London, England : 1993), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Rhomboid Proteases in Plasmodium spp. : Biology, Functional Roles, and Therapeutic Potential.Acta parasitologica · 2026Review
- The lipid bilayer strengthens the cooperative network of membrane proteins.Science advances · 2025Article
- Steric trapping strategy for studying the folding of helical membrane proteins.Methods (San Diego, Calif.) · 2024Review
- Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates.Cell reports · 2021Article
- Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease.The Journal of membrane biology · 2020Review
- The role of rhomboid superfamily members in protein homeostasis: Mechanistic insight and physiological implications.Biochimica et biophysica acta. Molecular cell research · 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
- Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- The rhomboid protease GlpG has weak interaction energies in its active site hydrogen bond network.The Journal of general physiology · 2019Article
- Membrane properties that shape the evolution of membrane enzymes.Current opinion in structural biology · 2018Review
- Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases.The Journal of membrane biology · 2018Article
- Reversible Unfolding of Rhomboid Intramembrane Proteases.Biophysical journal · 2016Article
- Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis.Molecular cell · 2016Article
- Conformational Changes in Transmembrane Domain 4 of Presenilin 1 Are Associated with Altered Amyloid-β 42 Production.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Cooperative folding of a polytopic α-helical membrane protein involves a compact N-terminal nucleus and nonnative loops.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures.The EMBO journal · 2014Article
- A subset of membrane-altering agents and γ-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases.Cell reports · 2014Article
- Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity.Cell · 2013Article
- Biochemical and structural insights into intramembrane metalloprotease mechanisms.Biochimica et biophysica acta · 2013Review
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4 authors.
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Abstract
Rhomboid proteases regulate key cellular pathways, but their biochemical mechanism including how water is made available to the membrane-immersed active site remains ambiguous. We performed four prolonged molecular dynamics simulations initiated from both gate-open and gate-closed states of Escherichia coli rhomboid GlpG in a phospholipid bilayer. GlpG was notably stable in both gating states, experiencing similar tilt and local membrane thinning, with no observable gating transitions, highlighting that gating is rate-limiting. Analysis of dynamics revealed rapid loss of crystallographic waters from the active site, but retention of a water cluster within a site formed by His141, Ser181, Ser185, and/or Gln189. Experimental interrogation of 14 engineered mutants revealed an essential role for at least Gln189 and Ser185 in catalysis with no effect on structural stability. Our studies indicate that spontaneous water supply to the intramembrane active site of rhomboid proteases is rare, but its availability for catalysis is ensured by an unanticipated active site element, the water-retention site.
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