Structural basis for intramembrane proteolysis by rhomboid serine proteases
- Adam Ben-Shem*,†,
- Deborah Fass‡, and
- Eitan Bibi*,†
- Departments of *Biological Chemistry and
- ‡Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
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Communicated by Arthur Karlin, Columbia University College of Physicians and Surgeons, New York, NY, November 7, 2006 (received for review October 15, 2006)
Abstract
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.
Footnotes
- †To whom correspondence may be addressed. E-mail: adam.ben-shem{at}weizmann.ac.il or e.bibi{at}weizmann.ac.il
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Author contributions: A.B.-S. and E.B. designed research; A.B.-S. performed research; A.B.-S. and D.F. analyzed data; and A.B.-S., D.F., and E.B. wrote the paper.
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The authors declare no conflict of interest.
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Data deposition: The coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2IRV).
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See Commentary on page 401.
- Abbreviation:
- TM,
- transmembrane helix
- © 2006 by The National Academy of Sciences of the USA
