Mobilization of the A-kinase
            <i>N-</i>
            myristate through an isoform-specific intermolecular switch

Gangal, Milind; Clifford, Teresa; Deich, Jason; Cheng, Xiaodong; Taylor, Susan S.; Johnson, David A.

doi:10.1073/pnas.96.22.12394

Cited by 56 publications

(71 citation statements)

References 27 publications

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“…The N-terminus is a genetically diverse region of the protein that precedes the conserved core and targets the protein to distinct subcellular locations through myristylation, phosphorylation, and deamidation (Carr et al, 1982;Yonemoto et al, 1993;Guthrie et al, 1997;Gangal et al, 1999;Pepperkok et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Cloning and functional identification of a novel BCA3 splice

Zhang¹,

Hu²,

Qiao³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The human breast cancer-associated gene (BCA3) was first discovered in breast and prostate cancer cells lines. In vivo studies have shown that BCA3 is mainly expressed in breast tumor cells and not in normal breast and prostate tissues. To date, 3 splice variants of BCA3 have been reported: a double-absent variant lacking exon 3 and exon 5 (BCA3-1), an exon 3-absent variant (BCA3-2), and full-length BCA3. In this study, we investigated whether a novel BCA3 splice variant exists that lacks only the exon 5-encoding sequence. BCA3 variant splices were subcloned and sequenced using reverse transcription-polymerase chain reaction. The preliminary biological functions of the splices were identified using confocal microscopy and a luciferase assay. The absence of exon 3 and exon 5 influenced the subcellular localization of BCA3 and nuclear factor kappa B (NF-kB)-dependent gene expression. Exon 3 and exon 5 of BCA3 may function together to provide a nuclear localization signal or transport sequence to enter the nucleus, and exon 3 may contain specific sequence(s) or domain(s) that influence the NF-κB signal cascade. The discovery of 10649 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (4): 10648-10656 (2014) Novel BCA3 splice novel BCA3 splicing indicates a new cancer research area, which may increase the understanding of cancer generation and development.

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Section: Discussionmentioning

confidence: 99%

Cloning and functional identification of a novel BCA3 splice

Zhang¹,

Hu²,

Qiao³

et al. 2014

Genet. Mol. Res.

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“…However, this model is supported by a number of previous findings. In a recent study, Gangal et al (50) showed that interaction of the RII subunit, but not the RI subunit, with the myristylated C subunit led to an increase in both NH 2 -terminal backbone flexibility and exposure of the NH 2 -myristate. In an earlier report, Herberg et al (51) demonstrated that deletion of the NH 2 -terminal A helix of the C subunit significantly affected the interaction between the C subunit and RII subunit, but not the RI subunit.…”

Section: Camp-dependent Protein Kinase Isoformsmentioning

confidence: 99%

Differential Binding of cAMP-dependent Protein Kinase Regulatory Subunit Isoforms Iα and IIβ to the Catalytic Subunit

Cheng¹,

Phelps²,

Taylor³

2001

Journal of Biological Chemistry

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Limited trypsin digestion of type I cAMP-dependent protein kinase holoenzyme results in a proteolytic-resistant ⌬(1-72) regulatory subunit core, indicating that interaction between the regulatory and catalytic subunits extends beyond the autoinhibitory site in the R subunit at the NH 2 terminus. Sequence alignment of the two R subunit isoforms, RI and RII, reveals a significantly sequence diversity at this specific region. To determine whether this sequence diversity is functionally important for interaction with the catalytic subunit, specific mutations, R133A and D328A, are introduced into sites adjacent to the active site cleft in the catalytic subunit. While replacing Arg 133 with Ala decreases binding affinity for RII, interaction between the catalytic subunit and RI is not affected. In contrast, mutant C(D328A) showed a decrease in affinity for binding RI while maintaining similar affinities for RII as compared with the wild-type catalytic subunit. These results suggest that sequence immediately NH 2 -terminal to the consensus inhibition site in RI and RII interacts with different sites at the proximal region of the active site cleft in the catalytic subunit. These isoform-specific differences would dictate a significantly different domain organization in the type I and type II holoenzymes. The regulatory (R)1 subunits of cAMP-dependent protein kinase (PKA) are multifunctional proteins that control in a variety of ways the physiological functions of this ubiquitous protein kinase (1, 2). While the R subunits have long been recognized as the primary receptor for cAMP and the major physiological inhibitor for the catalytic (C) subunit in eukaryotic cells, it is now apparent that these highly modular proteins play other important roles as well (3). The R subunits of PKA have a well defined domain structure that consists of a dimerization domain at the NH 2 terminus followed by an autoinhibitor site and two-tandem cAMP-binding domains. While the portion of the R subunit COOH-terminal to the inhibition site is responsible for high affinity binding of the C subunit and cAMP, the remaining NH 2 terminus serves as an adaptor for binding to kinase anchoring proteins (3) and other adaptor proteins, such as the SH3-containing Grb2 (4). This segment or region of the R subunit is responsible for in vivo subcellular localization and targeting of PKA.There are two general classes of PKA, designated as type I and type II, due exclusively to differences in the R subunits, RI and RII (5-7). Four different regulatory subunits, RI␣ (8), RI␤ (9), RII␣ (10), and RII␤ (11) have been identified. Regulatory isoforms are differentially expressed in tissues (12-14), and their subcellular distribution also appears to be distinct (8 -11, 15-18). The existence of a family of protein kinase A anchoring proteins (AKAPs) that tether the type II regulatory subunits to specific subcellular structures has been well documented (3), and AKAPs for both RI and RII (19,20) as well as an RI-specific AKAP protein (21) have been identified recently...

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“…If that domain can undergo conformational changes that expose it or bury it, then membrane binding can be switched on and off (47). Protein-protein interactions can also act as a switch for myristoylated proteins, as they do for protein kinase A (48). Exposure of an amino-terminal myristoylation sequence by proteolytic clipping of BID causes translocation from the cytosol to mitochondria (49).…”

Section: Discussionmentioning

confidence: 99%

Dual Sites of Protein Initiation Control the Localization and Myristoylation of Methionine Sulfoxide Reductase A

Kim

Cole

Lim

et al. 2010

Journal of Biological Chemistry

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Methionine sulfoxide reductase A is an essential enzyme in the antioxidant system, which scavenges reactive oxygen species through cyclic oxidation and reduction of methionine and methionine sulfoxide. In mammals, one gene encodes two forms of the reductase, one targeted to the cytosol and the other to mitochondria. The cytosolic form displays faster mobility than the mitochondrial form, suggesting a lower molecular weight for the former. The apparent size difference and targeting to two cellular compartments had been proposed to result from differential splicing of mRNA. We now show that differential targeting is effected by use of two initiation sites, one of which includes a mitochondrial targeting sequence, whereas the other does not. We also demonstrate that the mass of the cytosolic form is not less than that of the mitochondrial form; the faster mobility of cytosolic form is due to its myristoylation. Lipidation of methionine sulfoxide reductase A occurs in the mouse, in transfected tissue culture cells, and even in a cell-free protein synthesis system. The physiologic role of myristoylation of MsrA remains to be elucidated.All organisms living in an aerobic atmosphere are subjected to oxidative stress from reactive oxygen and nitrogen species. Proteins are a notable target of these species, and mechanisms have evolved to intercept them and to cope with proteins that do undergo oxidative modification (1). If the covalent modification is not reversible then the protein is targeted for selective degradation. Repair systems have evolved to cope with the reversible modifications, including oxidation and reduction of the sulfur-containing amino acids cysteine and methionine. The latter is relatively readily oxidized to methionine sulfoxide (MetO).2 Virtually all organisms from bacteria to mammals have several methionine sulfoxide reductases (Msr), which catalyze the reduction of MetO to Met (2). Reduction of methionine residues in proteins allows them to react again with reactive species, creating a system with catalytic efficiency in scavenging potentially damaging species. Thioredoxin and thioredoxin reductase act sequentially to regenerate active Msr, with the net result being the catalytic scavenging of reactive oxygen species at the expense of NADPH. A scheme of the system is shown in Fig. 1 Oxidation of Met to MetO creates a chiral center, and the Sand R-epimers are substrates for specific Msr (2, 4). In most organisms, the S-epimer is reduced by MsrA, and the R-epimer is reduced by MsrB, both using thioredoxin as the source of reducing equivalents. MsrA was described well before MsrB so that the majority of the studies in the literature were performed with MsrA. Those studies provide strong evidence supporting the physiological importance of cyclic oxidation and reduction of Met residues. Knocking out MsrA caused increased susceptibility to oxidative stress in mice (5), yeast (6), and bacteria (7-9). Conversely, overexpressing MsrA conferred increased resistance to Drosophila (10), Saccharomyces (11), ...

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Mobilization of the A-kinase N- myristate through an isoform-specific intermolecular switch

Cited by 56 publications

References 27 publications

Cloning and functional identification of a novel BCA3 splice

Cloning and functional identification of a novel BCA3 splice

Differential Binding of cAMP-dependent Protein Kinase Regulatory Subunit Isoforms Iα and IIβ to the Catalytic Subunit

Dual Sites of Protein Initiation Control the Localization and Myristoylation of Methionine Sulfoxide Reductase A

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