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A more recent version of this article appeared on January 1, 2004
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Submitted on May 28, 2003
Revised on August 6, 2003
Accepted on August 26, 2003
1 Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206 and Departments of Pathology and Pharmacology, University of Colorado School of Medicine, Denver, Colorado 80262
2 Department of Cardiology, University of Heidelberg, Bergheimer Strasse 58, 69115 Heidelberg, Germany
3 Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021
* Corresponding author. E-mail address: lesliec{at}njc.org.
Translocation of cytosolic phospholipase A2
(cPLA2) to Golgi and ER in response to intracellular
calcium ([Ca2+]i) mobilization is regulated
by its calcium-dependent lipid-binding, or C2, domain. Although well
studied in vitro, the biochemical characteristics of the
cPLA2 C2 domain offer no predictive value in determining
its intracellular targeting. To understand the molecular basis for
cPLA2C2 targeting in vivo, the intracellular targets of the
synaptotagmin 1 C2A (Syt1C2A) and protein kinase C
C2 (
C2)
domains were identified in MDCK cells and compared with that of hybrid
C2 domains containing the calcium binding loops (CBLs) from
cPLA2C2 on Syt1C2A and C backbones. In response to
an [Ca2+]i increase, targeted
plasma membrane regions rich in
phosphatidylinositol-4,5-bisphosphate (PIP2), and
Syt1C2A displayed a biphasic targeting pattern, first targeting
PIP2-rich regions in the plasma membrane, then the
trans-Golgi network (TGN). In contrast, the
Syt1C2A/cPLA2C2 and /cPLA2C2 hybrids
targeted Golgi/ER and colocalized with cPLA2C2. The
electrostatic properties of these hybrids suggested that the membrane
binding mechanism was similar to cPLA2C2, but not
or Syt1C2A. These results suggest that primarily CBLs 1 and 3
encode structural information specifying Golgi/ER targeting of
cPLA2C2 and the hybrid domains.
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