Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 35, Pages 14837-14842Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903289106
Keywords
membrane protein; PDZ domain; regulated intramembrane proteolysis; S2P
Categories
Funding
- Ministry of Science and Technology [2009CB918801]
- Tsinghua University 985 Phase II funds
- National Natural Science Foundation of China Project [30888001]
- Beijing Municipal Commissions of Education and Science and Technology
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Regulated intramembrane proteolysis (RIP) by the Site-2 protease (S2P) results in the release of a transmembrane signaling protein. Curiously, however, S2P cleavage must be preceded by the action of the Site-1 protease (S1P). To decipher the underlying mechanism, we reconstituted sequential, in vitro cleavages of the Escherichia coli transmembrane protein RseA by DegS (S1P) and RseP (S2P). After DegS cleavage, the newly exposed carboxyl-terminal residue Val-148 of RseA plays an essential role for RseP cleavage, and its mutation to charged or dissimilar amino acids crippled the Site-2 cleavage. By contrast, the identity of residues 146 and 147 of RseA has no impact on Site-2 cleavage. These results explain why Site-1 cleavage must precede Site-2 cleavage. Structural analysis reveals that the putative peptide-binding groove in the second, but not the first, PDZ domain of RseP is poised for binding to a single hydrophobic amino acid. These observations suggest that after DegS cleavage, the newly exposed carboxyl terminus of RseA may facilitate Site-2 cleavage through direct interaction with the PDZ domain.
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