Crystal Structure of the cGMP-dependent Protein Kinase II Leucine Zipper and Rab11b Protein Complex Reveals Molecular Details of G-kinase-specific Interactions

Reger, Albert S.; Yang, Matthew P.; Koide-Yoshida, Shizuyo; Guo, Elaine; Mehta, Shrenik; Yuasa, Keizo; Liu, Alan; Casteel, Darren E.; Kim, Choel

doi:10.1074/jbc.m114.575894

Cited by 20 publications

(22 citation statements)

References 44 publications

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“…This raises the obvious question of whether in fact the surfaces of coiled‐coil proteins are widely used as molecular scaffolds. Surprisingly, examples of their use to scaffold multi‐subunit protein complexes or to recruit enzymatic activities are relatively scarce. Analogous to the interaction of Shroom with ROCK, the coiled‐coil domain of MRCK has been proposed to contain a binding site for the leucine repeat adaptor protein 35a (LRAP35a), which links MRCK to MYO18A in a tripartite complex responsible for the assembly of lamellar actomyosin bundles essential for cell protrusion .…”

Section: Less Common Than You Might Think – Coiled‐coils As Molecularmentioning

confidence: 99%

Coiled‐coils: The long and short of it

2016

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Coiled‐coils are found in proteins throughout all three kingdoms of life. Coiled‐coil domains of some proteins are almost invariant in sequence and length, betraying a structural and functional role for amino acids along the entire length of the coiled‐coil. Other coiled‐coils are divergent in sequence, but conserved in length, thereby functioning as molecular spacers. In this capacity, coiled‐coil proteins influence the architecture of organelles such as centrioles and the Golgi, as well as permit the tethering of transport vesicles. Specialized coiled‐coils, such as those found in motor proteins, are capable of propagating conformational changes along their length that regulate cargo binding and motor processivity. Coiled‐coil domains have also been identified in enzymes, where they function as molecular rulers, positioning catalytic activities at fixed distances. Finally, while coiled‐coils have been extensively discussed for their potential to nucleate and scaffold large macromolecular complexes, structural evidence to substantiate this claim is relatively scarce.

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Section: Less Common Than You Might Think – Coiled‐coils As Molecularmentioning

confidence: 99%

Coiled‐coils: The long and short of it

2016

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“…5–7 All human PKGs have tandem CNB domains (CNB-A and -B) with different binding profiles for cGMP and its analogs. 1,2,8 The CNB domain consists of an eight-stranded β barrel and variable numbers of α helices.…”

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confidence: 99%

Structural Basis of Analog Specificity in PKG I and II

et al. 2017

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Cyclic GMP analogs, 8-Br, 8-pCPT, and PET-cGMP, have been widely used for characterizing cellular functions of cGMP-dependent protein kinase (PKG) I and II isotypes. However, interpreting results obtained using these analogs has been difficult due to their low isotype specificity. Additionally, each isotype has two binding sites with different cGMP affinities and analog selectivities, making understanding the molecular basis for isotype specificity of these compounds even more challenging. To determine isotype specificity of cGMP analogs and their structural basis, we generated the full-length regulatory domains of PKG I and II isotypes with each binding site disabled, determined their affinities for these analogs, and obtained cocrystal structures of both isotypes bound with cGMP analogs. Our affinity and activation measurements show that PET-cGMP is most selective for PKG I, whereas 8-pCPT-cGMP is most selective for PKG II. Our structures of cyclic nucleotide binding (CNB) domains reveal that the B site of PKG I is more open and forms a unique π/π interaction through Arg285 at β4 with the PET moiety, whereas the A site of PKG II has a larger β5/β6 pocket that can better accommodate the bulky 8-pCPT moiety. Our structural and functional results explain the selectivity of these analogs for each PKG isotype and provide a starting point for the rational design of isotype selective activators.

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“…An additional proof of the relative importance of the charge distribution on the LZ domain of PKG determining the interaction with GKAPs has been published recently (23). PKG II shows a completely different amino acid sequence and charge distribution when compared with the PKG I isoforms, and the crystal structure of the PKG II leucine zipper-Rab11b complex shows that PKG II binds to Rab11b mainly through van der Waals forces instead of electrostatic interactions.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, MYPT1 and GKAP42 bind to PKG I␣ (19 -21), IRAG and TFII-I are specific for PKG I␤ (12,22), whereas Rab11b forms a complex with PKG II (23). Given the low number of GKAPs known, there is still no convincing definition of a common PKG I/GKAP binding domain.…”

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confidence: 99%

Huntingtin-associated Protein 1 (HAP1) Is a cGMP-dependent Kinase Anchoring Protein (GKAP) Specific for the cGMP-dependent Protein Kinase Iβ Isoform

Corradini

Burgers

Plank

et al. 2015

Journal of Biological Chemistry

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Background: Protein kinase compartmentalization through anchoring proteins provides spatiotemporal specificity. Results: Competitive elution combined with cyclic nucleotide affinity enrichment identifies HAP1 as a putative novel PKG anchoring protein (GKAP). Conclusion: Secondary structure predictions, in vitro binding studies, and site-directed mutagenesis define the binding domain and classify HAP1 as a GKAP specifically anchoring PKG I␤. Significance: The repertoire of PKG anchoring proteins is expanded, enforcing that also PKG signaling is tightly spatiotemporally regulated.

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Crystal Structure of the cGMP-dependent Protein Kinase II Leucine Zipper and Rab11b Protein Complex Reveals Molecular Details of G-kinase-specific Interactions

Cited by 20 publications

References 44 publications

Coiled‐coils: The long and short of it

Coiled‐coils: The long and short of it

Structural Basis of Analog Specificity in PKG I and II

Huntingtin-associated Protein 1 (HAP1) Is a cGMP-dependent Kinase Anchoring Protein (GKAP) Specific for the cGMP-dependent Protein Kinase Iβ Isoform

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