The structural requirements of substrates of cyclic AMP‐dependent protein kinase

Zetterqvist, Örjan; Ragnarsson, Ulf

doi:10.1016/0014-5793(82)80872-7

Cited by 49 publications

(28 citation statements)

References 18 publications

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“…However, according to generally accepted models of K+ channel orientation in the membrane, both sites would be intracellular and, therefore, carbohydrate-free. One potential phosphorylation site exists at Thr-38 for cAMP-dependent protein kinase (23).…”

Section: Resultsmentioning

confidence: 99%

Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart.

Roberds

Tamkun

1991

Proc. Natl. Acad. Sci. U.S.A.

207

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Five distinct K+ channel cDNA molecules (RK1 to RK5) were cloned from either rat heart or rat aorta cDNA libraries. Four of the channels, RK1 to RK4, are similar or identical to Shaker-like K+ channels previously identified in rat brain cDNA libraries. Major differences among RK1 to RK4 exist in the amino-and carboxyl-terminal regions and in amino acids representing potential extracellular sequence between the S1 and S2 hydrophobic domains. RK5 encodes a unique channel of 490 amino acids having six hydrophobic domains but only five basic residues in the putative voltagesensing domain. Unlike RK1 to RK4, RK5 is a rat homologue of the Drosophila Shal family of K+ channels, which have not been previously described in mammals. Although RK5 mRNA is present in cardiac atrium and ventricle, it is most abundant in brain. RK1, RK2, and RK3 transcripts are predominantly found in brain but are present also at lower levels in other tissues, such as heart and aorta. RK2 is absent from skeletal muscle whereas RK1 and RK3 are present in this tissue. RK4 mRNA is ubiquitous in electrically excitable tissue, being present at comparable levels in atrium, ventricle, aorta, brain, and skeletal muscle. The cloning of RK5 confirms the presence in mammals of all four Drosophila K+ channel families: Shaker, Shab, Shaw, and Shal.Potassium channels constitute the most diverse group of voltage-gated ion channels. At least four general classes of K+ channels have been defiuied by electrophysiological means, with each class being comprised of many subtypes.These classes include inward rectifiers, Ca2+-activated K+ channels, A-type K+ channels, and delayed rectifiers (1). This diversity of K+ channel electrophysiology suggests that these channels are also structurally diverse. The discovery of a Drosophila strain possessing a mutant K+ channel prompted the cloning of the Drosophila Shaker gene (2), initiating the study of K+ channels at the molecular level. To date, the complete cDNA sequences for 1 mouse (3), 2 human (4, 5), and 11 rat (6-15) K+ channel cDNA clones have been reported. Heterogeneity in mammals appears to be generated primarily by the expression of a large number of genes, since known mammalian K+ channel genes are intronless (4,5,12,14,16) and alternative splicing in mammals has not been reported.Whereas previous K+ channel cloning efforts have focused on the nervous system, this paper reports the sequence and tissue distribution of five K+ channel clones (RK1 to RK5) from the rat cardiovascular system.t RK1 to RK4 are homologues of the Drosophila Shaker K+ channel family. RK5 has not been described previously, to our knowledge, and is a mammalian homologue of the Drosophila Shal gene. This study further illustrates the diversity of structure and tissuespecific expression of mammalian K+ channels.MATERIALS AND METHODS cDNA Library Construction and Screening. Size-fractionated libraries [2-to 8-kilobase (kb) cDNA] were constructed according to standard protocols (17). PCR-generated cDNA fragments corresponding to nucle...

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Section: Resultsmentioning

confidence: 99%

Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart.

Roberds

Tamkun

1991

Proc. Natl. Acad. Sci. U.S.A.

207

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“…Also the location of a third basic group, preferably arginine, six residues removed is important for substrate recognition in some cases (14). The positioning of these three arginines in PKI satisfies both criteria: the residues are conserved in RI, while RI contains four arginine side chains within its hinge region (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…9 and 10). Basic residues, in particular arginine side chains, preceding the serine or threonine appear to be essential (8,(11)(12)(13)(14); a minimal structure of -R-R-X-S-X-has been proposed, where X represents essentially any amino acid and R represents arginine (reviewed in ref. 15).…”

mentioning

confidence: 99%

Identification of an inhibitory region of the heat-stable protein inhibitor of the cAMP-dependent protein kinase.

Scott¹,

Fischer²,

Demaille³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

162

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The present study was undertaken in order to identify the inhibitory site of the heat-stable inhibitor of cAMP-dependent protein kinase (PKI) and to synthesize a peptide that could serve as a useful inhibitor of the enzyme. Digestion of purified PKI by mast cell proteinase II yielded a peptide fragment that retained inhibitory activity. A sequence of 20 amino acids of the peptide, ...Ble-Ala-Ser-Gly-Arg-ThrGly-Arg-Arg-Asn-Ala-Ile-His-Asp-Ile-Leu-Val-Ser-SerAla..., revealed the presence of a "pseudosubstrate site" (Arg-Arg-Asn-Ala-Ile) for the cAMP-dependent protein kinase in which alanine replaces the seryl or threonyl residue that is normally phosphorylated. Digestion of PKI with various other proteinases implicated the involvement of arginyl and hydrophobic residues as determinants for the inhibitory activity. The assumption that this region is part of the inhibitory site was confirmed by the synthesis of a corresponding duodecapeptide that displayed strong inhibitory activity. Inhibition by the peptide was competitive with a K; of 0.8 ,LM as measured against a number of protein substrates. The sequence of this fragment bears a strong resemblance to the autophosphorylation site in the type II regulatory subunit of cAMP-dependent protein kinase, a region also postulated to interact with the catalytic subunit, and the analogous region of type I regulatory subunit. Neither intact PKI nor the synthetic peptide inhibit the cGMP-dependent protein kinase, phosphorylase kinase, myosin light-chain kinase, casein kinase II, or protein kinase C.

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“…Moreover, this AQP0-AKAP2-PKA signaling axis is potentially involved in the pathology of the autosomal dominant cataractogenic AQP0 mutation Arg233Lys (Lin et al, 2007). This mutation corresponds to part of the substrate recognition sequence of PKA for residue Ser235 (Zetterqvist and Ragnarsson, 1982).…”

Section: Box 2 Coordination Of Camp Signaling Proteins By Akapsmentioning

confidence: 99%

Local cAMP signaling in disease at a glance

Gold

Gonen

Scott

2013

Journal of Cell Science

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Summary The second messenger cyclic AMP (cAMP) operates in discrete subcellular regions within which proteins that synthesize, break down or respond to the second messenger are precisely organized. A burgeoning knowledge of compartmentalized cAMP signaling is revealing how the local control of signaling enzyme activity impacts upon disease. The aim of this Cell Science at a Glance article and the accompanying poster is to highlight how misregulation of local cyclic AMP signaling can have pathophysiological consequences. We first introduce the core molecular machinery for cAMP signaling, which includes the cAMP-dependent protein kinase (PKA), and then consider the role of A-kinase anchoring proteins (AKAPs) in coordinating different cAMP-responsive proteins. The latter sections illustrate the emerging role of local cAMP signaling in four disease areas: cataracts, cancer, diabetes and cardiovascular diseases.

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The structural requirements of substrates of cyclic AMP‐dependent protein kinase

Cited by 49 publications

References 18 publications

Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart.

Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart.

Identification of an inhibitory region of the heat-stable protein inhibitor of the cAMP-dependent protein kinase.

Local cAMP signaling in disease at a glance

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