IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29368-4.html
   My bibliography  Save this article

Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation

Author

Listed:
  • Aleksandra Levina

    (Max Perutz Labs
    Medical University of Vienna)

  • Kaelin D. Fleming

    (University of Victoria)

  • John E. Burke

    (University of Victoria
    The University of British Columbia)

  • Thomas A. Leonard

    (Max Perutz Labs
    Medical University of Vienna)

Abstract

3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It is often referred to as a ‘master’ kinase due to its ability to activate at least 23 downstream protein kinases implicated in various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that PDK1 trans-autophosphorylation is mediated by a PIP3-mediated face-to-face dimer. We report regulatory motifs in the kinase-PH interdomain linker that allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. Finally, we show that PDK1 is autoinhibited by its PH domain and that positive cooperativity of PIP3 binding drives switch-like activation of PDK1. These results imply that the PDK1-mediated activation of effector kinases, including Akt, PKC, Sgk, S6K and RSK, many of whom are not directly regulated by phosphoinositides, is also likely to be dependent on PIP3 or PI(3,4)P2.

Suggested Citation

  • Aleksandra Levina & Kaelin D. Fleming & John E. Burke & Thomas A. Leonard, 2022. "Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29368-4
    DOI: 10.1038/s41467-022-29368-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29368-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-29368-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    3. Eunyoung Park & Shaun Rawson & Kunhua Li & Byeong-Won Kim & Scott B. Ficarro & Gonzalo Gonzalez-Del Pino & Humayun Sharif & Jarrod A. Marto & Hyesung Jeon & Michael J. Eck, 2019. "Architecture of autoinhibited and active BRAF–MEK1–14-3-3 complexes," Nature, Nature, vol. 575(7783), pages 545-550, November.
    4. Zhen-Lin Chen & Jia-Ming Meng & Yong Cao & Ji-Li Yin & Run-Qian Fang & Sheng-Bo Fan & Chao Liu & Wen-Feng Zeng & Yue-He Ding & Dan Tan & Long Wu & Wen-Jing Zhou & Hao Chi & Rui-Xiang Sun & Meng-Qiu Do, 2019. "A high-speed search engine pLink 2 with systematic evaluation for proteome-scale identification of cross-linked peptides," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Sarah E. Conduit & Wayne Pearce & Amandeep Bhamra & Benoit Bilanges & Laura Bozal-Basterra & Lazaros C. Foukas & Mathias Cobbaut & Sandra D. Castillo & Mohammad Amin Danesh & Mahreen Adil & Arkaitz Ca, 2024. "A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ravi R. Sonani & Lee K. Palmer & Nathaniel C. Esteves & Abigail A. Horton & Amanda L. Sebastian & Rebecca J. Kelly & Fengbin Wang & Mark A. B. Kreutzberger & William K. Russell & Petr G. Leiman & Birg, 2024. "An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Matthew Day & Bilal Tetik & Milena Parlak & Yasser Almeida-Hernández & Markus Räschle & Farnusch Kaschani & Heike Siegert & Anika Marko & Elsa Sanchez-Garcia & Markus Kaiser & Isabel A. Barker & Laure, 2024. "TopBP1 utilises a bipartite GINS binding mode to support genome replication," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Michael J. Roy & Minglyanna G. Surudoi & Ashleigh Kropp & Jianmei Hou & Weiwen Dai & Joshua M. Hardy & Lung-Yu Liang & Thomas R. Cotton & Bernhard C. Lechtenberg & Toby A. Dite & Xiuquan Ma & Roger J., 2023. "Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Yichen Zhong & Hakimeh Moghaddas Sani & Bishnu P. Paudel & Jason K. K. Low & Ana P. G. Silva & Stefan Mueller & Chandrika Deshpande & Santosh Panjikar & Xavier J. Reid & Max J. Bedward & Antoine M. Oi, 2022. "The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Eunyoung Park & Shaun Rawson & Anna Schmoker & Byeong-Won Kim & Sehee Oh & Kangkang Song & Hyesung Jeon & Michael J. Eck, 2023. "Cryo-EM structure of a RAS/RAF recruitment complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    7. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    11. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    12. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    13. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    14. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    15. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    17. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Alexander Kroll & Sahasra Ranjan & Martin K. M. Engqvist & Martin J. Lercher, 2023. "A general model to predict small molecule substrates of enzymes based on machine and deep learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    19. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    20. Maciej K. Kocylowski & Hande Aypek & Wolfgang Bildl & Martin Helmstädter & Philipp Trachte & Bernhard Dumoulin & Sina Wittösch & Lukas Kühne & Ute Aukschun & Carolin Teetzen & Oliver Kretz & Botond Ga, 2022. "A slit-diaphragm-associated protein network for dynamic control of renal filtration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29368-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.