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Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity.

Chen C, Ha BH, Thévenin AF, Lou HJ, Zhang R, Yip KY, Peterson JR, Gerstein M, Kim PM, Filippakopoulos P, Knapp S, Boggon TJ, Turk BE
Mol Cell 53 140-7 (2014)
Related entries: 4jdi, 4jdj, 4jdk

Cited: 59 times
EuropePMC logo PMID: 24374310

Abstract

Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many serine-threonine kinases display a significant preference for serine or threonine as the phosphoacceptor residue. Here we show that a residue located in the kinase activation segment, which we term the "DFG+1" residue, acts as a major determinant for serine-threonine phosphorylation site specificity. Mutation of this residue was sufficient to switch the phosphorylation site preference for multiple kinases, including the serine-specific kinase PAK4 and the threonine-specific kinase MST4. Kinetic analysis of peptide substrate phosphorylation and crystal structures of PAK4-peptide complexes suggested that phosphoacceptor residue preference is not mediated by stronger binding of the favored substrate. Rather, favored kinase-phosphoacceptor combinations likely promote a conformation optimal for catalysis. Understanding the rules governing kinase phosphoacceptor preference allows kinases to be classified as serine or threonine specific based on their sequence.

Reviews - 4jdh mentioned but not cited (1)

  1. Signaling, Regulation, and Specificity of the Type II p21-activated Kinases. Ha BH, Morse EM, Turk BE, Boggon TJ. J Biol Chem 290 12975-12983 (2015)

Articles - 4jdh mentioned but not cited (4)

  1. Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity. Chen C, Ha BH, Thévenin AF, Lou HJ, Zhang R, Yip KY, Peterson JR, Gerstein M, Kim PM, Filippakopoulos P, Knapp S, Boggon TJ, Turk BE. Mol Cell 53 140-147 (2014)
  2. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL. Sci Signal 8 rs13 (2015)
  3. Cryo-EM Structure of Nucleotide-Bound Tel1ATM Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. Yates LA, Williams RM, Hailemariam S, Ayala R, Burgers P, Zhang X. Structure 28 96-104.e3 (2020)
  4. PAK4 crystal structures suggest unusual kinase conformational movements. Zhang EY, Ha BH, Boggon TJ. Biochim Biophys Acta Proteins Proteom 1866 356-365 (2018)


Reviews citing this publication (8)

  1. Homing in: Mechanisms of Substrate Targeting by Protein Kinases. Miller CJ, Turk BE. Trends Biochem Sci 43 380-394 (2018)
  2. Protein phosphatases in the regulation of mitosis. Nilsson J. J Cell Biol 218 395-409 (2019)
  3. Revisiting protein kinase-substrate interactions: Toward therapeutic development. de Oliveira PS, Ferraz FA, Pena DA, Pramio DT, Morais FA, Schechtman D. Sci Signal 9 re3 (2016)
  4. Large-scale profiling of protein kinases for cellular signaling studies by mass spectrometry and other techniques. Sugiyama N, Ishihama Y. J Pharm Biomed Anal 130 264-272 (2016)
  5. Structural Aspects of LIMK Regulation and Pharmacology. Chatterjee D, Preuss F, Dederer V, Knapp S, Mathea S. Cells 11 142 (2022)
  6. Architecture and mechanism of the central gear in an ancient molecular timer. Egli M. J R Soc Interface 14 20161065 (2017)
  7. Substrate and phosphorylation site selection by phosphoprotein phosphatases. Nguyen H, Kettenbach AN. Trends Biochem Sci 48 713-725 (2023)
  8. LIMK2: A Multifaceted kinase with pleiotropic roles in human physiology and pathologies. Shah K, Cook M. Cancer Lett 565 216207 (2023)

Articles citing this publication (46)

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  2. Structural and Functional Analysis of the Cdk13/Cyclin K Complex. Greifenberg AK, Hönig D, Pilarova K, Düster R, Bartholomeeusen K, Bösken CA, Anand K, Blazek D, Geyer M. Cell Rep 14 320-331 (2016)
  3. Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis. Hein JB, Hertz EPT, Garvanska DH, Kruse T, Nilsson J. Nat Cell Biol 19 1433-1440 (2017)
  4. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R. Sci Signal 9 ra47 (2016)
  5. Unmasking determinants of specificity in the human kinome. Creixell P, Palmeri A, Miller CJ, Lou HJ, Santini CC, Nielsen M, Turk BE, Linding R. Cell 163 187-201 (2015)
  6. Identification of non-Ser/Thr-Pro consensus motifs for Cdk1 and their roles in mitotic regulation of C2H2 zinc finger proteins and Ect2. Suzuki K, Sako K, Akiyama K, Isoda M, Senoo C, Nakajo N, Sagata N. Sci Rep 5 7929 (2015)
  7. The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner. Bailey FP, Byrne DP, Oruganty K, Eyers CE, Novotny CJ, Shokat KM, Kannan N, Eyers PA. Biochem J 467 47-62 (2015)
  8. The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain. Schmidt SH, Knape MJ, Boassa D, Mumdey N, Kornev AP, Ellisman MH, Taylor SS, Herberg FW. Proc Natl Acad Sci U S A 116 14979-14988 (2019)
  9. An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E, Robinson RC. Nat Commun 6 8681 (2015)
  10. Large-scale Discovery of Substrates of the Human Kinome. Sugiyama N, Imamura H, Ishihama Y. Sci Rep 9 10503 (2019)
  11. Global analysis of human nonreceptor tyrosine kinase specificity using high-density peptide microarrays. Deng Y, Alicea-Velázquez NL, Bannwarth L, Lehtonen SI, Boggon TJ, Cheng HC, Hytönen VP, Turk BE. J Proteome Res 13 4339-4346 (2014)
  12. Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output. Miller CJ, Lou HJ, Simpson C, van de Kooij B, Ha BH, Fisher OS, Pirman NL, Boggon TJ, Rinehart J, Yaffe MB, Linding R, Turk BE. PLoS Biol 17 e2006540 (2019)
  13. An atlas of substrate specificities for the human serine/threonine kinome. Johnson JL, Yaron TM, Huntsman EM, Kerelsky A, Song J, Regev A, Lin TY, Liberatore K, Cizin DM, Cohen BM, Vasan N, Ma Y, Krismer K, Robles JT, van de Kooij B, van Vlimmeren AE, Andrée-Busch N, Käufer NF, Dorovkov MV, Ryazanov AG, Takagi Y, Kastenhuber ER, Goncalves MD, Hopkins BD, Elemento O, Taatjes DJ, Maucuer A, Yamashita A, Degterev A, Uduman M, Lu J, Landry SD, Zhang B, Cossentino I, Linding R, Blenis J, Hornbeck PV, Turk BE, Yaffe MB, Cantley LC. Nature 613 759-766 (2023)
  14. Evolution of protein kinase substrate recognition at the active site. Bradley D, Beltrao P. PLoS Biol 17 e3000341 (2019)
  15. Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen. Levin RS, Hertz NT, Burlingame AL, Shokat KM, Mukherjee S. Proc Natl Acad Sci U S A 113 E4776-83 (2016)
  16. MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway. Couzens AL, Xiong S, Knight JDR, Mao DY, Guettler S, Picaud S, Kurinov I, Filippakopoulos P, Sicheri F, Gingras AC. Mol Cell Proteomics 16 1098-1110 (2017)
  17. Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity. Howard CJ, Hanson-Smith V, Kennedy KJ, Miller CJ, Lou HJ, Johnson AD, Turk BE, Holt LJ. Elife 3 (2014)
  18. Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs. van de Kooij B, Creixell P, van Vlimmeren A, Joughin BA, Miller CJ, Haider N, Simpson CD, Linding R, Stambolic V, Turk BE, Yaffe MB. Elife 8 e44635 (2019)
  19. Serine-Selective Bioconjugation. Vantourout JC, Adusumalli SR, Knouse KW, Flood DT, Ramirez A, Padial NM, Istrate A, Maziarz K, deGruyter JN, Merchant RR, Qiao JX, Schmidt MA, Deery MJ, Eastgate MD, Dawson PE, Bernardes GJL, Baran PS. J Am Chem Soc 142 17236-17242 (2020)
  20. Dynamics of human protein kinase Aurora A linked to drug selectivity. Pitsawong W, Buosi V, Otten R, Agafonov RV, Zorba A, Kern N, Kutter S, Kern G, Pádua RA, Meniche X, Kern D. Elife 7 e36656 (2018)
  21. Identification of PNG kinase substrates uncovers interactions with the translational repressor TRAL in the oocyte-to-embryo transition. Hara M, Lourido S, Petrova B, Lou HJ, Von Stetina JR, Kashevsky H, Turk BE, Orr-Weaver TL. Elife 7 e33150 (2018)
  22. The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser³⁵⁹ Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity. Gong J, Yao Y, Zhang P, Udayasuryan B, Komissarova EV, Chen J, Sivaramakrishnan S, Van Eyk JE, Steinberg SF. Mol Cell Biol 35 1727-1740 (2015)
  23. Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response. Lazarus MB, Levin RS, Shokat KM. Cell Signal 29 78-83 (2017)
  24. Kinase Substrate Profiling Using a Proteome-wide Serine-Oriented Human Peptide Library. Barber KW, Miller CJ, Jun JW, Lou HJ, Turk BE, Rinehart J. Biochemistry 57 4717-4725 (2018)
  25. Identification and classification of small molecule kinases: insights into substrate recognition and specificity. Oruganty K, Talevich EE, Neuwald AF, Kannan N. BMC Evol Biol 16 7 (2016)
  26. Rational Redesign of a Functional Protein Kinase-Substrate Interaction. Chen C, Nimlamool W, Miller CJ, Lou HJ, Turk BE. ACS Chem Biol 12 1194-1198 (2017)
  27. Lessons from LIMK1 enzymology and their impact on inhibitor design. Salah E, Chatterjee D, Beltrami A, Tumber A, Preuss F, Canning P, Chaikuad A, Knaus P, Knapp S, Bullock AN, Mathea S. Biochem J 476 3197-3209 (2019)
  28. A pan-cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy. Kumar M, Papaleo E. Sci Rep 10 14874 (2020)
  29. Sequence and Structure-Based Analysis of Specificity Determinants in Eukaryotic Protein Kinases. Bradley D, Viéitez C, Rajeeve V, Selkrig J, Cutillas PR, Beltrao P. Cell Rep 34 108602 (2021)
  30. Characterization of the Catalytic and Nucleotide Binding Properties of the α-Kinase Domain of Dictyostelium Myosin-II Heavy Chain Kinase A. Yang Y, Ye Q, Jia Z, Côté GP. J Biol Chem 290 23935-23946 (2015)
  31. Serine substitutions are linked to codon usage and differ for variable and conserved protein regions. Schwartz GW, Shauli T, Linial M, Hershberg U. Sci Rep 9 17238 (2019)
  32. Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy. Spinelli E, Christensen KR, Bryant E, Schneider A, Rakotomamonjy J, Muir AM, Giannelli J, Littlejohn RO, Roeder ER, Schmidt B, Wilson WG, Marco EJ, Iwama K, Kumada S, Pisano T, Barba C, Vetro A, Brilstra EH, van Jaarsveld RH, Matsumoto N, Goldberg-Stern H, Carney PW, Andrews PI, El Achkar CM, Berkovic S, Rodan LH, Undiagnosed Diseases Network (UDN), McWalter K, Guerrini R, Scheffer IE, Mefford HC, Mandelstam S, Laux L, Millichap JJ, Guemez-Gamboa A, Nairn AC, Carvill GL. Ann Neurol 90 274-284 (2021)
  33. Plasmodium falciparum Cyclic GMP-Dependent Protein Kinase Interacts with a Subunit of the Parasite Proteasome. Govindasamy K, Khan R, Snyder M, Lou HJ, Du P, Kudyba HM, Muralidharan V, Turk BE, Bhanot P. Infect Immun 87 e00523-18 (2019)
  34. Recognition of physiological phosphorylation sites by p21-activated kinase 4. Chetty AK, Sexton JA, Ha BH, Turk BE, Boggon TJ. J Struct Biol 211 107553 (2020)
  35. Phosphorylation-dependent protein design: design of a minimal protein kinase-inducible domain. Gao F, Thornley BS, Tressler CM, Naduthambi D, Zondlo NJ. Org Biomol Chem 17 3984-3995 (2019)
  36. In vivo evidence for a regulatory role of phosphorylation of Arabidopsis Rubisco activase at the Thr78 site. Kim SY, Harvey CM, Giese J, Lassowskat I, Singh V, Cavanagh AP, Spalding MH, Finkemeier I, Ort DR, Huber SC. Proc Natl Acad Sci U S A 116 18723-18731 (2019)
  37. Phosphorylation of translation initiation factor eIF2α at Ser51 depends on site- and context-specific information. Uppala JK, Ghosh C, Sathe L, Dey M. FEBS Lett 592 3116-3125 (2018)
  38. Mass Spectrometry-Based Discovery of in vitro Kinome Substrates. Sugiyama N. Mass Spectrom (Tokyo) 9 A0082 (2020)
  39. Water-mediated conformational preselection mechanism in substrate binding cooperativity to protein kinase A. Setny P, Wiśniewska MD. Proc Natl Acad Sci U S A 115 3852-3857 (2018)
  40. A Genetic Toggle for Chemical Control of Individual Plk1 Substrates. Johnson JM, Hebert AS, Drane QH, Lera RF, Wan J, Weaver BA, Coon JJ, Burkard ME. Cell Chem Biol 27 350-362.e8 (2020)
  41. Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state. Besch A, Marsiglia WM, Mohammadi M, Zhang Y, Traaseth NJ. Proc Natl Acad Sci U S A 120 e2213090120 (2023)
  42. Molecular Basis for Ser/Thr Specificity in PKA Signaling. Knape MJ, Wallbott M, Burghardt NCG, Bertinetti D, Hornung J, Schmidt SH, Lorenz R, Herberg FW. Cells 9 E1548 (2020)
  43. Differential phosphoproteome analysis of rat brain regions after organophosphorus compound sarin intoxication. Chaubey K, Alam SI, Waghmare CK, Bhattacharya BK. Toxicol Res (Camb) 12 253-263 (2023)
  44. Evolution of CDK1 Paralog Specializations in a Lineage With Fast Developing Planktonic Embryos. Ma X, Øvrebø JI, Thompson EM. Front Cell Dev Biol 9 770939 (2021)
  45. Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Ha BH, Yigit S, Natarajan N, Morse EM, Calderwood DA, Boggon TJ. Commun Biol 5 1257 (2022)
  46. Self-assembly-based posttranslational protein oscillators. Kimchi O, Goodrich CP, Courbet A, Curatolo AI, Woodall NB, Baker D, Brenner MP. Sci Adv 6 eabc1939 (2020)


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