4lhw Citations

Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB.

J Biol Chem 288 32466-32474 (2013)
Related entries: 4lhv, 4lhx, 4lhy, 4lhz, 4li0

Cited: 41 times
EuropePMC logo PMID: 24072714

Abstract

Small G-proteins of the Ras superfamily control the temporal and spatial coordination of intracellular signaling networks by acting as molecular on/off switches. Guanine nucleotide exchange factors (GEFs) regulate the activation of these G-proteins through catalytic replacement of GDP by GTP. During nucleotide exchange, three distinct substrate·enzyme complexes occur: a ternary complex with GDP at the start of the reaction (G-protein·GEF·GDP), an intermediary nucleotide-free binary complex (G-protein·GEF), and a ternary GTP complex after productive G-protein activation (G-protein·GEF·GTP). Here, we show structural snapshots of the full nucleotide exchange reaction sequence together with the G-protein substrates and products using Rabin8/GRAB (GEF) and Rab8 (G-protein) as a model system. Together with a thorough enzymatic characterization, our data provide a detailed view into the mechanism of Rabin8/GRAB-mediated nucleotide exchange.

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  1. Rab GTPases and their interacting protein partners: Structural insights into Rab functional diversity. Pylypenko O, Hammich H, Yu IM, Houdusse A. Small GTPases 9 22-48 (2018)
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  1. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Liu Z, Bryant N, Kumaran R, Beilina A, Abeliovich A, Cookson MR, West AB. Hum Mol Genet 27 385-395 (2018)
  2. Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB. Guo Z, Guo Z, Hou X, Goody RS, Itzen A. J Biol Chem 288 32466-32474 (2013)
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Reviews citing this publication (4)

  1. Rab proteins and the compartmentalization of the endosomal system. Wandinger-Ness A, Zerial M. Cold Spring Harb Perspect Biol 6 a022616 (2014)
  2. Molecular control of Rab activity by GEFs, GAPs and GDI. Müller MP, Goody RS. Small GTPases 9 5-21 (2018)
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  1. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S, Baptista MA, Fiske BK, Fell MJ, Morrow JA, Reith AD, Alessi DR, Mann M. Elife 5 e12813 (2016)
  2. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. Lai YC, Kondapalli C, Lehneck R, Procter JB, Dill BD, Woodroof HI, Gourlay R, Peggie M, Macartney TJ, Corti O, Corvol JC, Campbell DG, Itzen A, Trost M, Muqit MM. EMBO J 34 2840-2861 (2015)
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  5. SCD1 and SCD2 Form a Complex That Functions with the Exocyst and RabE1 in Exocytosis and Cytokinesis. Mayers JR, Hu T, Wang C, Cárdenas JJ, Tan Y, Pan J, Bednarek SY. Plant Cell 29 2610-2625 (2017)
  6. Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia. Mamais A, Kluss JH, Bonet-Ponce L, Landeck N, Langston RG, Smith N, Beilina A, Kaganovich A, Ghosh MC, Pellegrini L, Kumaran R, Papazoglou I, Heaton GR, Bandopadhyay R, Maio N, Kim C, LaVoie MJ, Gershlick DC, Cookson MR. PLoS Biol 19 e3001480 (2021)
  7. Cdk5 Regulation of the GRAB-Mediated Rab8-Rab11 Cascade in Axon Outgrowth. Furusawa K, Asada A, Urrutia P, Gonzalez-Billault C, Fukuda M, Hisanaga SI. J Neurosci 37 790-806 (2017)
  8. Promotion of Cell Proliferation through Inhibition of Cell Autophagy Signalling Pathway by Rab3IP is Restrained by MicroRNA-532-3p in Gastric Cancer. Guo W, Chen Z, Chen Z, Yu J, Liu H, Li T, Lin T, Chen H, Zhao M, Li G, Hu Y. J Cancer 9 4363-4373 (2018)
  9. Structural outline of the detailed mechanism for elongation factor Ts-mediated guanine nucleotide exchange on elongation factor Tu. Thirup SS, Van LB, Nielsen TK, Knudsen CR. J Struct Biol 191 10-21 (2015)
  10. Nucleotide based covalent inhibitors of KRas can only be efficient in vivo if they bind reversibly with GTP-like affinity. Müller MP, Jeganathan S, Heidrich A, Campos J, Goody RS. Sci Rep 7 3687 (2017)
  11. A pull-down procedure for the identification of unknown GEFs for small GTPases. Koch D, Rai A, Ali I, Bleimling N, Friese T, Brockmeyer A, Janning P, Goud B, Itzen A, Müller MP, Goody RS. Small GTPases 7 93-106 (2016)
  12. Inferring joint sequence-structural determinants of protein functional specificity. Neuwald AF, Aravind L, Altschul SF. Elife 7 e29880 (2018)
  13. Rabin8 suppresses autophagosome formation independently of its guanine nucleotide-exchange activity towards Rab8. Amagai Y, Itoh T, Fukuda M, Mizuno K. J Biochem 158 139-153 (2015)
  14. Guanine nucleotide exchange factors activate Rab8a for Toll-like receptor signalling. Tong SJ, Wall AA, Hung Y, Luo L, Stow JL. Small GTPases 12 27-43 (2021)
  15. Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses. Park SJ, Park H, Kim MG, Zhang S, Park SE, Kim S, Chung C. iScience 23 101000 (2020)
  16. Structural basis of guanine nucleotide exchange for Rab11 by SH3BP5. Goto-Ito S, Morooka N, Yamagata A, Sato Y, Sato K, Fukai S. Life Sci Alliance 2 e201900297 (2019)
  17. Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs. Chandrakumar AA, Coyaud É, Marshall CB, Ikura M, Raught B, Rottapel R. J Cell Biol 220 e202008037 (2021)
  18. Crystal structure of tetrameric human Rabin8 GEF domain. Vetter M, Boegholm N, Christensen A, Bhogaraju S, Andersen MB, Lorentzen A, Lorentzen E. Proteins 86 405-413 (2018)
  19. Crystal structure of the GDP-bound GTPase domain of Rab5a from Leishmania donovani. Zohib M, Maheshwari D, Pal RK, Freitag-Pohl S, Biswal BK, Pohl E, Arora A. Acta Crystallogr F Struct Biol Commun 76 544-556 (2020)
  20. Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases. Takahashi T, Shirai J, Matsuda M, Nakanaga S, Matsushita S, Wakita K, Hayashishita M, Suzuki R, Noguchi A, Yokota N, Kawahara H. iScience 26 106652 (2023)