The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex

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 a...

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Autores: Williams, Judith C., Armesilla, Angel L., 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
Tipo de recurso: artículo
Fecha de publicación:2006
País:España
Institución:Universidad Camilo José Cela (UCJC)
Repositorio:Depósito Digital e-UCJC
OAI Identifier:oai:repositorio.ucjc.edu:20.500.12020/1660
Acceso en línea:http://hdl.handle.net/20.500.12020/1660
https://doi.org/10.1074/jbc.M513341200
Access Level:acceso abierto
Palabra clave:Biología Celular y Molecular
Ciencias Biomédicas
PMCA4
nNOS
Syntrophin
Protein Interaction
32 Ciencias Médicas
2302.21 Biología Molecular
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oai_identifier_str oai:repositorio.ucjc.edu:20.500.12020/1660
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spelling The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein ComplexWilliams, Judith C.Armesilla, Angel L.Mohamed, Tamer M. A.Hagarty, Cassandra L.McIntyre, Fiona H.Schomburg, SybilleZaki, Aly O.Oceandy, DelvacCartwright, Elizabeth J.Buch, Mamta H.Emerson, MichaelNeyses, LudwigBiología Celular y MolecularCiencias BiomédicasPMCA4nNOSSyntrophinProtein Interaction32 Ciencias Médicas2302.21 Biología MolecularThe 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.Elsevier2006info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12020/1660https://doi.org/10.1074/jbc.M513341200reponame:Depósito Digital e-UCJCinstname:Universidad Camilo José Cela (UCJC)Inglésinfo:eu-repo/semantics/openAccessoai:repositorio.ucjc.edu:20.500.12020/16602026-05-27T07:36:51Z
dc.title.none.fl_str_mv The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
title The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
spellingShingle The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
Williams, Judith C.
Biología Celular y Molecular
Ciencias Biomédicas
PMCA4
nNOS
Syntrophin
Protein Interaction
32 Ciencias Médicas
2302.21 Biología Molecular
title_short The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
title_full The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
title_fullStr The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
title_full_unstemmed The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
title_sort The Sarcolemmal Calcium Pump, alpha-1 Syntrophin, and Neuronal Nitric-oxide Synthase Are Parts of a Macromolecular Protein Complex
dc.creator.none.fl_str_mv Williams, Judith C.
Armesilla, Angel L.
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
author Williams, Judith C.
author_facet Williams, Judith C.
Armesilla, Angel L.
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
author_role author
author2 Armesilla, Angel L.
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
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Biología Celular y Molecular
Ciencias Biomédicas
PMCA4
nNOS
Syntrophin
Protein Interaction
32 Ciencias Médicas
2302.21 Biología Molecular
topic Biología Celular y Molecular
Ciencias Biomédicas
PMCA4
nNOS
Syntrophin
Protein Interaction
32 Ciencias Médicas
2302.21 Biología Molecular
description 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.
publishDate 2006
dc.date.none.fl_str_mv 2006
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12020/1660
https://doi.org/10.1074/jbc.M513341200
url http://hdl.handle.net/20.500.12020/1660
https://doi.org/10.1074/jbc.M513341200
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Depósito Digital e-UCJC
instname:Universidad Camilo José Cela (UCJC)
instname_str Universidad Camilo José Cela (UCJC)
reponame_str Depósito Digital e-UCJC
collection Depósito Digital e-UCJC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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