Structural basis for intramembrane proteolysis by rhomboid serine proteases

Intramembrane proteases catalyze peptide bond cleavage of integral membrane protein substrates. This activity is crucial for many biological and pathological processes. Rhomboids are evolutionarily widespread intramembrane serine proteases. Here, we present the 2.3-Å-resolution crystal structure of...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-01, Vol.104 (2), p.462-466
Main Authors: Ben-Shem, Adam, Fass, Deborah, Bibi, Eitan
Format: Article
Language:English
Subjects:
Active sites
Amino Acid Sequence
Animals
Architecture
Base Sequence
Biological Sciences
Catalytic Domain
Crystal structure
Crystallography, X-Ray
DNA Primers - genetics
DNA, Bacterial - genetics
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endopeptidases - chemistry
Endopeptidases - genetics
Endopeptidases - metabolism
Enzymes
Escherichia coli
Escherichia coli - enzymology
Escherichia coli - genetics
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - genetics
Escherichia coli Proteins - metabolism
Humans
Hydrogen bonds
Lipids
Membrane proteins
Membrane Proteins - chemistry
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membranes - enzymology
Models, Molecular
Molecular Sequence Data
Molecules
P branes
Protein Conformation
Proteins
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Sequence Homology, Amino Acid
Serine Endopeptidases - chemistry
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Solubility
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Summary:Intramembrane proteases catalyze peptide bond cleavage of integral membrane protein substrates. This activity is crucial for many biological and pathological processes. Rhomboids are evolutionarily widespread intramembrane serine proteases. Here, we present the 2.3-Å-resolution crystal structure of a rhomboid from Escherichia coli. The enzyme has six transmembrane helices, five of which surround a short TM4, which starts deep within the membrane at the catalytic serine residue. Thus, the catalytic serine is in an externally exposed cavity, which provides a hydrophilic environment for proteolysis. Our results reveal a mechanism to enable water-dependent catalysis at the depth of the hydrophobic milieu of the membrane and suggest how substrates gain access to the sequestered rhomboid active site.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0609773104