The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.

2.50
Hdl Handle:
http://hdl.handle.net/2436/7703
Title:
The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.
Authors:
Williams, Judith C.; Armesilla, Angel Luis; Mohamed, Tamer M. A.; Hagarty, Cassandra L.; McIntyre, Fiona H.; Schomburg, Sybille; Zaki, Aly O.; Oceandy, Delvac; Cartwright, Elizabeth J.; Buch, Mamta H.; Emerson, Michael; Neyses, Ludwig
Abstract:
The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality.
Citation:
The Journal of Biological Chemistry, 281(33): 23341-23348
Publisher:
American Society for Biochemistry and Molecular Biology
Issue Date:
2006
URI:
http://hdl.handle.net/2436/7703
DOI:
10.1074/jbc.M513341200
PubMed ID:
16735509
Additional Links:
http://www.jbc.org/cgi/reprint/281/33/23341
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorWilliams, Judith C.-
dc.contributor.authorArmesilla, Angel Luis-
dc.contributor.authorMohamed, Tamer M. A.-
dc.contributor.authorHagarty, Cassandra L.-
dc.contributor.authorMcIntyre, Fiona H.-
dc.contributor.authorSchomburg, Sybille-
dc.contributor.authorZaki, Aly O.-
dc.contributor.authorOceandy, Delvac-
dc.contributor.authorCartwright, Elizabeth J.-
dc.contributor.authorBuch, Mamta H.-
dc.contributor.authorEmerson, Michael-
dc.contributor.authorNeyses, Ludwig-
dc.date.accessioned2007-01-23T16:39:09Z-
dc.date.available2007-01-23T16:39:09Z-
dc.date.issued2006-
dc.identifier.citationThe Journal of Biological Chemistry, 281(33): 23341-23348en
dc.identifier.issn0021-9258-
dc.identifier.pmid16735509-
dc.identifier.doi10.1074/jbc.M513341200-
dc.identifier.urihttp://hdl.handle.net/2436/7703-
dc.description.abstractThe main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality.en
dc.format.extent337694 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.relation.urlhttp://www.jbc.org/cgi/reprint/281/33/23341en
dc.subjectPlasma Membraneen
dc.subjectSarcolemmal calcium pumpen
dc.subjectAlpha-1 syntrophinen
dc.subjectNeuronal nitric-oxide synthaseen
dc.titleThe sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.en
dc.typeArticleen
dc.format.digYES-
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