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Calmodulin Binds and Stabilizes CCTα, the Rate‐Limiting Enzyme for Phosphatidylcholine Synthesis
Author(s) -
Chen Bill,
Mallampalli Rama K.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb7-a
Subject(s) - calmodulin , calpain , biochemistry , enzyme , chemistry , phosphocholine , phosphatidylcholine , microbiology and biotechnology , biology , phospholipid , membrane
CTP:phosphocholine cytidylyltransferase (CCTα) is a proteolytically‐sensitive enzyme essential for production of phosphatidylcholine, the major phospholipid of animal cell membranes. The molecular signals that govern CCTα protein stability are unknown. Calmodulin (CaM), rather than disruption of an NH 2 ‐terminal PEST sequence, stabilized CCTα from actions of the proteinase, calpain. Adenoviral gene transfer of CaM in cells protected CCT α , whereas CaM siRNA accentuated CCT α degradation by calpains. Mapping and site‐directed mutagenesis of CCTα uncovered a motif (LQERVDKVK) harboring a vital recognition site, Q243, whereby CaM directly binds to the enzyme. Mutagenesis of CCTα Q243 not only resulted in loss of CaM binding, but also led tocomplete calpain resistance in vitro and in vivo . Thus, calpains and CaM both access CCTα using a structurally unique molecular mechanism that profoundly affects CCTα levels. These data suggest that CaM, by antagonizing calpain, serves as a novel binding partner for CCTα that stabilizes the enzyme under pro‐inflammatory stress.