Molecular Basis of AKAP Specificity for PKA Regulatory Subunits

Gold, Matthew G.; Lygren, Birgitte; Dokurno, P.; Hoshi, Naoto; McConnachie, George; Taskén, Kjetil; Carlson, Cathrine R.; Scott, John D.; Barford, David

doi:10.1016/j.molcel.2006.09.006

Cited by 255 publications

(315 citation statements)

References 47 publications

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“…In addition, the Dpy-30 domain of Sdc1, which is a domain that was initially found in DPY-30 proteins required for sex determination and dosage compensation in Caenorhabditis elegans, has also been predicted to be a protein-protein interaction domain (39,40). Dpy-30 domains are similar to RIIa domains found in cAMP protein kinase A regulatory subunits that are known to dimerize (41)(42)(43). Therefore, the Dpy-30 domain of Sdc1 could be facilitating dimerization or interactions with Bre2.…”

Section: Resultsmentioning

confidence: 98%

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

South¹,

Fingerman

Mersman

et al. 2010

Journal of Biological Chemistry

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In Saccharomyces cerevisiae, lysine 4 on histone H3 (H3K4) is methylated by the Set1 complex (Set1C or COMPASS). Besides the catalytic Set1 subunit, several proteins that form the Set1C (Swd1, Swd2, Swd3, Spp1, Bre2, and Sdc1) are also needed to mediate proper H3K4 methylation. Until this study, it has been unclear how individual Set1C members interact and how this interaction may impact histone methylation and gene expression. In this study, Bre2 and Sdc1 are shown to directly interact, and it is shown that the association of this heteromeric complex is needed for proper H3K4 methylation and gene expression to occur. Interestingly, mutational and biochemical analysis identified the C terminus of Bre2 as a critical protein-protein interaction domain that binds to the Dpy-30 domain of Sdc1. Using the human homologs of Bre2 and Sdc1, ASH2L and DPY-30, respectively, we demonstrate that the C terminus of ASH2L also interacts with the Dpy-30 domain of DPY-30, suggesting that this protein-protein interaction is maintained from yeast to humans. Because of the functionally conserved nature of the C terminus of Bre2 and ASH2L, this region was named the SDI (Sdc1 Dpy-30 interaction) domain. Finally, we show that the SDI-Dpy-30 domain interaction is physiologically important for the function of Set1 in vivo, because specific disruption of this interaction prevents Bre2 and Sdc1 association with Set1, resulting in H3K4 methylation defects and decreases in gene expression. Overall, these and other mechanistic studies on how H3K4 methyltransferase complexes function will likely provide insights into how human MLL and SET1-like complexes or overexpression of ASH2L leads to oncogenesis.In Saccharomyces cerevisiae, histone H3 lysine 4 (H3K4) 3 mono-, di-, and trimethylation is mediated by the Set1 histone methyltransferase (1, 2). Set1 and H3K4 methylation were first identified to be required for silencing at rDNA, telomeres, and mating-type loci (3-6). Set1 and H3K4 trimethylation are also found to be located at euchromatin and enriched in the 5Ј-ends of coding regions of transcriptionally active genes (7,8). In addition, Set1 and its human homologs, MLL1, MLL2, and hSET1, associate with the phosphorylated C-terminal domain of RNA polymerase II (7, 9 -11). More recently, it has been shown that various chromodomain and PHD zinc finger-containing proteins can bind to histones and H3K4 di-and trimethylated histone peptides and histones (12)(13)(14). Therefore, these and other studies suggest that Set1-mediated histone methylation plays a positive role in mediating gene expression through recruitment of effector proteins.Unlike other yeast histone methyltransferases, Set1 requires a multiprotein complex for its activity in vitro and in vivo (1,(15)(16)(17)(18). The yeast Set1 complex, also called Set1C or COMPASS (complex associated with Set1), consists of eight subunits (Set1, Bre2, Sdc1, Swd1, Swd2, Swd3, Spp1, and Shg1) (15,18,19). After the discovery of yeast Set1C, it was determined that the human H3K4 methyltransferases MLL1 ...

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Section: Resultsmentioning

confidence: 98%

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

South¹,

Fingerman

Mersman

et al. 2010

Journal of Biological Chemistry

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“…To date 47 human AKAP genes have been identified that encode proteins which direct PKA to defined intracellular locations (22,23). The majority of these sequester type II PKA subtypes (24)(25)(26), although several dual-function AKAPs can bind either RI or RII (27)(28)(29). Here we report that sphingosine kinase interacting protein (SKIP) anchors the type I PKA holoenzyme exclusively.…”

mentioning

confidence: 94%

An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria

Means

Lygren

Langeberg

et al. 2011

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

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A-kinase anchoring proteins (AKAPs) tether the cAMP-dependent protein kinase (PKA) to intracellular sites where they preferentially phosphorylate target substrates. Most AKAPs exhibit nanomolar affinity for the regulatory (RII) subunit of the type II PKA holoenzyme, whereas dual-specificity anchoring proteins also bind the type I (RI) regulatory subunit of PKA with 10-100-fold lower affinity. A range of cellular, biochemical, biophysical, and genetic approaches comprehensively establish that sphingosine kinase interacting protein (SKIP) is a truly type I-specific AKAP. Mapping studies located anchoring sites between residues 925-949 and 1,140-1,175 of SKIP that bind RI with dissociation constants of 73 and 774 nM, respectively. Molecular modeling and site-directed mutagenesis approaches identify Phe 929 and Tyr 1,151 as RI-selective binding determinants in each anchoring site. SKIP complexes exist in different states of RI-occupancy as single-molecule pulldown photobleaching experiments show that 41 AE 10% of SKIP sequesters two YFP-RI dimers, whereas 59 AE 10% of the anchoring protein binds a single YFP-RI dimer. Imaging, proteomic analysis, and subcellular fractionation experiments reveal that SKIP is enriched at the inner mitochondrial membrane where it associates with a prominent PKA substrate, the coiled-coil helix protein ChChd3.

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“…They are the Qua1 domain from STAR proteins (43,44), the protein kinase A (PKA) type I␣ and type II␣ regulatory subunits (45,46), and the Siah-interacting protein (SIP) (47). Of these structures, Get5-C has the shortest sequence and the highest ratio of buried to exposed surface area (30% versus 28% for the next most, the crystal structure of the PKA type II␣ regulatory subunit) (48). It is significantly more thermostable than the only other dimer where this was measured, the Qua1 domain, with a T m of 74°C compared with 63°C (43).…”

Section: Discussionmentioning

confidence: 99%

Get5 Carboxyl-terminal Domain Is a Novel Dimerization Motif That Tethers an Extended Get4/Get5 Complex

Chartron

VanderVelde

Rao

et al. 2012

Journal of Biological Chemistry

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Molecular Basis of AKAP Specificity for PKA Regulatory Subunits

Cited by 255 publications

References 47 publications

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria

Get5 Carboxyl-terminal Domain Is a Novel Dimerization Motif That Tethers an Extended Get4/Get5 Complex

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