3q4z › Citations

Structural insights into the autoactivation mechanism of p21-activated protein kinase.

Wang J, Wu JW, Wang ZX
Structure 19 1752-61 (2011)
Related entries: 3q52, 3q53

Cited: 40 times
EuropePMC logo PMID: 22153498

Abstract

p21-activated kinases (PAKs) play an important role in diverse cellular processes. Full activation of PAKs requires autophosphorylation of a critical threonine/serine located in the activation loop of the kinase domain. Here we report crystal structures of the phosphorylated and unphosphorylated PAK1 kinase domain. The phosphorylated PAK1 kinase domain has a conformation typical of all active protein kinases. Interestingly, the structure of the unphosphorylated PAK1 kinase domain reveals an unusual dimeric arrangement expected in an authentic enzyme-substrate complex, in which the activation loop of the putative "substrate" is projected into the active site of the "enzyme." The enzyme is bound to AMP-PNP and has an active conformation, whereas the substrate is empty and adopts an inactive conformation. Thus, the structure of the asymmetric homodimer mimics a trans-autophosphorylation complex, and suggests that unphosphorylated PAK1 could dynamically adopt both the active and inactive conformations in solution.

Articles - 3q4z mentioned but not cited (5)

  1. 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)
  2. Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis. Sorrell FJ, Kilian LM, Elkins JM. Biochem J 476 1037-1051 (2019)
  3. Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus. Alur V, Raju V, Vastrad B, Tengli A, Tengli A, Vastrad C, Kotturshetti S. Biosci Rep 41 BSR20210617 (2021)
  4. Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1. Shahinozzaman M, Ahmed S, Emran R, Tawata S. Sci Rep 11 17471 (2021)
  5. Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors. Burggraaff L, Lenselink EB, Jespers W, van Engelen J, Bongers BJ, González MG, Liu R, Hoos HH, van Vlijmen HWT, IJzerman AP, van Westen GJP. J Chem Inf Model 60 4283-4295 (2020)


Reviews citing this publication (13)

  1. How Do Protein Kinases Take a Selfie (Autophosphorylate)? Beenstock J, Mooshayef N, Engelberg D. Trends Biochem Sci 41 938-953 (2016)
  2. P21-activated kinase 4--not just one of the PAK. Dart AE, Wells CM. Eur J Cell Biol 92 129-138 (2013)
  3. Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations. Eswaran J, Li DQ, Shah A, Kumar R. Clin Cancer Res 18 3743-3749 (2012)
  4. P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer. Yao D, Li C, Rajoka MSR, He Z, Huang J, Wang J, Zhang J. Theranostics 10 9741-9766 (2020)
  5. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)
  6. P21-activated kinase in inflammatory and cardiovascular disease. Taglieri DM, Ushio-Fukai M, Monasky MM. Cell Signal 26 2060-2069 (2014)
  7. Participation of group I p21-activated kinases in neuroplasticity. Koth AP, Oliveira BR, Parfitt GM, Buonocore Jde Q, Barros DM. J Physiol Paris 108 270-277 (2014)
  8. Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors. Arter C, Trask L, Ward S, Yeoh S, Bayliss R. J Biol Chem 298 102247 (2022)
  9. p21-Activated Kinases in Thyroid Cancer. Bautista L, Knippler CM, Ringel MD. Endocrinology 161 bqaa105 (2020)
  10. Unique catalytic activities and scaffolding of p21 activated kinase-1 in cardiovascular signaling. Ke Y, Lei M, Wang X, Solaro RJ. Front Pharmacol 4 116 (2013)
  11. Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class. He Y, Grassam-Rowe A, Lei M, Bae JSH. Philos Trans R Soc Lond B Biol Sci 378 20220285 (2023)
  12. PAK1 and Therapy Resistance in Melanoma. Kichina JV, Maslov A, Kandel ES. Cells 12 2373 (2023)
  13. The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype. Dobrigna M, Poëa-Guyon S, Rousseau V, Vincent A, Toutain A, Barnier JV. Front Neurosci 17 1123784 (2023)

Articles citing this publication (22)

  1. IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly. Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H. Mol Cell 55 891-903 (2014)
  2. Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate. Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, Krauthammer M, Halaban R, Schlessinger J, Turk BE, Boggon TJ. Proc Natl Acad Sci U S A 109 16107-16112 (2012)
  3. Mutations in FLS2 Ser-938 dissect signaling activation in FLS2-mediated Arabidopsis immunity. Cao Y, Aceti DJ, Sabat G, Song J, Makino S, Fox BG, Bent AF. PLoS Pathog 9 e1003313 (2013)
  4. Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer. El-Baba C, Mahadevan V, Fahlbusch FB, Mohan S S, Rau TT, Gali-Muhtasib H, Schneider-Stock R. Mol Cancer 13 201 (2014)
  5. Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex. Alexa A, Gógl G, Glatz G, Garai Á, Zeke A, Varga J, Dudás E, Jeszenői N, Bodor A, Hetényi C, Reményi A. Proc Natl Acad Sci U S A 112 2711-2716 (2015)
  6. Myosin 3A kinase activity is regulated by phosphorylation of the kinase domain activation loop. Quintero OA, Unrath WC, Stevens SM, Manor U, Kachar B, Yengo CM. J Biol Chem 288 37126-37137 (2013)
  7. Structures of the inactive and active states of RIP2 kinase inform on the mechanism of activation. Pellegrini E, Signor L, Singh S, Boeri Erba E, Cusack S. PLoS One 12 e0177161 (2017)
  8. Structural Basis of Protein Kinase R Autophosphorylation. Mayo CB, Erlandsen H, Mouser DJ, Feinstein AG, Robinson VL, May ER, Cole JL. Biochemistry 58 2967-2977 (2019)
  9. The p21-activated kinase PAK3 forms heterodimers with PAK1 in brain implementing trans-regulation of PAK3 activity. Combeau G, Kreis P, Domenichini F, Amar M, Fossier P, Rousseau V, Barnier JV. J Biol Chem 287 30084-30096 (2012)
  10. 3D structure analysis of PAKs: A clue to the rational design for affinity reagents and blockers. Jha RK, Strauss CE. Cell Logist 2 69-77 (2012)
  11. Autophosphorylation Affects Substrate-Binding Affinity of Tobacco Ca2+-Dependent Protein Kinase1. Ito T, Ishida S, Oe S, Fukazawa J, Takahashi Y. Plant Physiol 174 2457-2468 (2017)
  12. Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study. Shahinozzaman M, Ishii T, Takano R, Halim MA, Hossain MA, Tawata S. Sci Pharm 86 E32 (2018)
  13. Derivation of stationary distributions of biochemical reaction networks via structure transformation. Hong H, Kim J, Ali Al-Radhawi M, Sontag ED, Kim JK. Commun Biol 4 620 (2021)
  14. Face-to-face, pak-to-pak. Malecka KA, Peterson JR. Structure 19 1723-1724 (2011)
  15. Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors. Gul M, Fakhar M, Najumuddin, Rashid S. PLoS One 14 e0225132 (2019)
  16. p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II. Saldivar-Cerón HI, Villamar-Cruz O, Wells CM, Oguz I, Spaggiari F, Chernoff J, Patiño-López G, Huerta-Yepez S, Montecillo-Aguado M, Rivera-Pazos CM, Loza-Mejía MA, Vivar-Sierra A, Briseño-Díaz P, Zentella-Dehesa A, Leon-Del-Rio A, López-Saavedra A, Padierna-Mota L, Ibarra-Sánchez MJ, Esparza-López J, Hernández-Rivas R, Arias-Romero LE. Front Cell Dev Biol 9 759259 (2021)
  17. Identification of Pak1 inhibitors using water thermodynamic analysis. Biswal J, Jayaprakash P, Suresh Kumar R, Venkatraman G, Poopandi S, Rangasamy R, Jeyaraman J. J Biomol Struct Dyn 38 13-31 (2020)
  18. Improvement of insulin signaling in myoblast cells by an addition of SKIP-binding peptide within Pak1 kinase domain. Ijuin T, Takenawa T. Biochem Biophys Res Commun 456 41-46 (2015)
  19. Synthesis and structure-activity relationship of 2-arylamino-4-aryl-pyrimidines as potent PAK1 inhibitors. Xu Y, Foulks JM, Clifford A, Brenning B, Lai S, Luo B, Parnell KM, Merx S, McCullar MV, Kanner SB, Ho KK. Bioorg Med Chem Lett 23 4072-4075 (2013)
  20. WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches. Biswal J, Jayaprakash P, Rayala SK, Venkatraman G, Rangaswamy R, Jeyaraman J. ACS Omega 6 26829-26845 (2021)
  21. A critical evaluation of protein kinase regulation by activation loop autophosphorylation. Reinhardt R, Leonard TA. Elife 12 e88210 (2023)
  22. Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation. Wang DN, Ni JJ, Li JH, Gao YQ, Ni FJ, Zhang ZZ, Fang JY, Lu J, Yao YF. PLoS Pathog 19 e1011189 (2023)


Quick links