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Structures of the PKC-iota kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533-551 in the C-terminal tail and their roles in ATP binding.

Takimura T, Kamata K, Fukasawa K, Ohsawa H, Komatani H, Yoshizumi T, Takahashi I, Kotani H, Iwasawa Y
Acta Crystallogr D Biol Crystallogr 66 577-83 (2010)
Cited: 35 times
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Abstract

Protein kinase C (PKC) plays an essential role in a wide range of cellular functions. Although crystal structures of the PKC-theta, PKC-iota and PKC-betaII kinase domains have previously been determined in complexes with small-molecule inhibitors, no structure of a PKC-substrate complex has been determined. In the previously determined PKC-iota complex, residues 533-551 in the C-terminal tail were disordered. In the present study, crystal structures of the PKC-iota kinase domain in its ATP-bound and apo forms were determined at 2.1 and 2.0 A resolution, respectively. In the ATP complex, the electron density of all of the C-terminal tail residues was well defined. In the structure, the side chain of Phe543 protrudes into the ATP-binding pocket to make van der Waals interactions with the adenine moiety of ATP; this is also observed in other AGC kinase structures such as binary and ternary substrate complexes of PKA and AKT. In addition to this interaction, the newly defined residues around the turn motif make multiple hydrogen bonds to glycine-rich-loop residues. These interactions reduce the flexibility of the glycine-rich loop, which is organized for ATP binding, and the resulting structure promotes an ATP conformation that is suitable for the subsequent phosphoryl transfer. In the case of the apo form, the structure and interaction mode of the C-terminal tail of PKC-iota are essentially identical to those of the ATP complex. These results indicate that the protein structure is pre-organized before substrate binding to PKC-iota, which is different from the case of the prototypical AGC-branch kinase PKA.

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  3. The Cryptosporidium parvum kinome. Artz JD, Wernimont AK, Allali-Hassani A, Zhao Y, Amani M, Lin YH, Senisterra G, Wasney GA, Fedorov O, King O, Roos A, Lunin VV, Qiu W, Finerty P, Hutchinson A, Chau I, von Delft F, MacKenzie F, Lew J, Kozieradzki I, Vedadi M, Schapira M, Zhang C, Shokat K, Heightman T, Hui R. BMC Genomics 12 478 (2011)
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  6. A cancer-associated mutation in atypical protein kinase Cι occurs in a substrate-specific recruitment motif. Linch M, Sanz-Garcia M, Soriano E, Zhang Y, Riou P, Rosse C, Cameron A, Knowles P, Purkiss A, Kjaer S, McDonald NQ, Parker PJ. Sci Signal 6 ra82 (2013)
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  10. Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C. Xiong X, Li X, Wen YA, Gao T. J. Biol. Chem. 291 25167-25178 (2016)
  11. Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study. Thangsunan P, Tateing S, Hannongbua S, Suree N. J. Biomol. Struct. Dyn. 34 1561-1575 (2016)
  12. Binding site matching in rational drug design: algorithms and applications. Naderi M, Lemoine JM, Govindaraj RG, Kana OZ, Feinstein WP, Brylinski M. Brief. Bioinformatics (2018)
  13. Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination. Ufimtsev IS, Almagor L, Weis WI, Levitt M. Proc. Natl. Acad. Sci. U.S.A. 116 10819-10823 (2019)
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  15. Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2. Almagor L, Ufimtsev IS, Ayer A, Li J, Weis WI. Proc. Natl. Acad. Sci. U.S.A. 116 10804-10812 (2019)
  16. A critical evaluation of protein kinase regulation by activation loop autophosphorylation. Reinhardt R, Leonard TA. Elife 12 e88210 (2023)
  17. Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation. Levina A, Fleming KD, Burke JE, Leonard TA. Nat Commun 13 1874 (2022)
  18. Small-molecule inhibition of pyruvate phosphate dikinase targeting the nucleotide binding site. Minges A, Groth G. PLoS ONE 12 e0181139 (2017)
  19. Structural basis of conformational variance in phosphorylated and non-phosphorylated states of PKCβII. Grewal BK, Krishnan RV, Sobhia ME. Proteins 82 1332-1347 (2014)
  20. The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression. Smalley T, Metcalf R, Patel R, Islam SMA, Bommareddy RR, Acevedo-Duncan M. Front Oncol 10 209 (2020)


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