ArticleBiological chemistry2008
In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells.
Article in Biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- The opening dynamics of the lateral gate regulates the activity of rhomboid proteases.Science advances · 2023Article
- Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases.The Journal of membrane biology · 2018Article
- A Golgi rhomboid protease Rbd2 recruits Cdc48 to cleave yeast SREBP.The EMBO journal · 2016Article
- Cytosolic extensions directly regulate a rhomboid protease by modulating substrate gating.Nature · 2015Article
- Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity.Cell · 2013Article
- Structure and mechanism of rhomboid protease.The Journal of biological chemistry · 2013Review
- Article
- Architectural and thermodynamic principles underlying intramembrane protease function.Nature chemical biology · 2012Article
- An internal water-retention site in the rhomboid intramembrane protease GlpG ensures catalytic efficiency.Structure (London, England : 1993) · 2012Article
- Membrane proteases in the bacterial protein secretion and quality control pathway.Microbiology and molecular biology reviews : MMBR · 2012Review
- Catalytic mechanism of rhomboid protease GlpG probed by 3,4-dichloroisocoumarin and diisopropyl fluorophosphonate.The Journal of biological chemistry · 2012Article
- The rhomboid protease family: a decade of progress on function and mechanism.Genome biology · 2011Review
- Derlin-1 is a rhomboid pseudoprotease required for the dislocation of mutant α-1 antitrypsin from the endoplasmic reticulum.Nature structural & molecular biology · 2011Article
- Taking the plunge: integrating structural, enzymatic and computational insights into a unified model for membrane-immersed rhomboid proteolysis.The Biochemical journal · 2010Review
- Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms.Nature reviews. Microbiology · 2009Review
- Core principles of intramembrane proteolysis: comparison of rhomboid and site-2 family proteases.Current opinion in structural biology · 2008Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Intramembrane proteases hydrolyze peptide bonds within cell membranes. Recent crystal structures revealed that rhomboid intramembrane proteases contain a hydrated active site that opens to the outside of the cell, but is protected laterally from membrane lipids by protein segments. Using Escherichia coli rhomboid (GlpG) structures as a guide, we previously took a mutational approach to identify the GlpG gating mechanism that allows substrates to enter the active site laterally from the membrane. Mutations that weaken contacts keeping the gate closed increase enzyme activity and implicate transmembrane segment 5 as the substrate gate. Since these analyses were performed in vitro with pure proteins in detergent micelles, we have now examined GlpG in its natural environment, within the membrane of live E. coli cells. In striking congruity with in vitro analysis, gate-opening mutants in transmembrane segment 5 display up to a 10-fold increase in protease activity in living cells. Conversely, mutations in other parts of the protease, including the membrane-inserted L1 loop previously thought to be the gate, decrease enzyme activity. These observations provide evidence for the existence of both closed and open forms of GlpG in cells, and show that inter-conversion between them via substrate gating is rate limiting physiologically.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.