Abstract
Muscle A-kinase anchoring protein (mAKAP) is a scaffold protein found principally at the nuclear envelope of striated myocytes. mAKAP maintains a complex consisting of multiple signal transduction molecules including the cAMP-dependent protein kinase A, the ryanodine receptor calcium release channel, phosphodiesterase type 4D3, and protein phosphatase 2A. By an unknown mechanism, a domain containing spectrin repeats is responsible for targeting mAKAP to the nuclear envelope. We now demonstrate that the integral membrane protein nesprin-1alpha serves as a receptor for mAKAP on the nuclear envelope in cardiac myocytes. Nesprin-1alpha is inserted into the nuclear envelope by a conserved, C-terminal, klarsicht-related transmembrane domain and forms homodimers by the binding of an amino-terminal spectrin repeat domain. Through the direct binding of the nesprin-1alpha amino-terminal dimerization domain to the third mAKAP spectrin repeat, nesprin-1alpha targets mAKAP to the nuclear envelope. In turn, overexpression of these spectrin repeat domains in myocytes can displace mAKAP from nesprin-1alpha.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Substitution
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Animals
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Base Sequence
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Binding, Competitive
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COS Cells
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Cyclic Nucleotide Phosphodiesterases, Type 4
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DNA, Complementary / genetics
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Dimerization
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Multiprotein Complexes
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Mutagenesis, Site-Directed
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Myocytes, Cardiac / metabolism*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Envelope / metabolism*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Point Mutation
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Protein Structure, Quaternary
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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Transfection
Substances
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing
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Akap6 protein, rat
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DNA, Complementary
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Multiprotein Complexes
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Nerve Tissue Proteins
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Nuclear Proteins
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Recombinant Proteins
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Syne1 protein, rat
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4