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The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways

Author

Listed:
  • C. Tarricone

    (National Institute for Medical Research
    European Institute of Oncology)

  • B. Xiao

    (National Institute for Medical Research)

  • N. Justin

    (National Institute for Medical Research)

  • P. A. Walker

    (National Institute for Medical Research)

  • K. Rittinger

    (National Institute for Medical Research)

  • S. J. Gamblin

    (National Institute for Medical Research)

  • S. J. Smerdon

    (National Institute for Medical Research)

Abstract

Small G proteins are GTP-dependent molecular switches that regulate numerous cellular functions1. They can be classified into homologous subfamilies that are broadly associated with specific biological processes. Cross-talk between small G-protein families has an important role in signalling, but the mechanism by which it occurs is poorly understood2. The coordinated action of Arf and Rho family GTPases is required to regulate many cellular processes including lipid signalling3, cell motility4 and Golgi function5. Arfaptin is a ubiquitously expressed protein implicated in mediating cross-talk between Rac (a member of the Rho family) and Arf small GTPases. Here we show that Arfaptin binds specifically to GTP-bound Arf1 and Arf6, but binds to Rac·GTP and Rac·GDP with similar affinities. The X-ray structure of Arfaptin reveals an elongated, crescent-shaped dimer of three-helix coiled-coils. Structures of Arfaptin with Rac bound to either GDP or the slowly hydrolysable analogue GMPPNP show that the switch regions adopt similar conformations in both complexes. Our data highlight fundamental differences between the molecular mechanisms of Rho and Ras family signalling, and suggest a model of Arfaptin-mediated synergy between the Arf and Rho family signalling pathways.

Suggested Citation

  • C. Tarricone & B. Xiao & N. Justin & P. A. Walker & K. Rittinger & S. J. Gamblin & S. J. Smerdon, 2001. "The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways," Nature, Nature, vol. 411(6834), pages 215-219, May.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6834:d:10.1038_35075620
    DOI: 10.1038/35075620
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    Cited by:

    1. Albert Solernou & Benjamin S Hanson & Robin A Richardson & Robert Welch & Daniel J Read & Oliver G Harlen & Sarah A Harris, 2018. "Fluctuating Finite Element Analysis (FFEA): A continuum mechanics software tool for mesoscale simulation of biomolecules," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-29, March.
    2. Yuan Lin & Theresa A. Ramelot & Simge Senyuz & Attila Gursoy & Hyunbum Jang & Ruth Nussinov & Ozlem Keskin & Yi Zheng, 2024. "Tumor-derived RHOA mutants interact with effectors in the GDP-bound state," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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