Cited by 256Protein Kinase Regulation and GTPase SignalingCellular transport and secretionReceptor Mechanisms and Signaling

Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo

Ismail, Shehab A, Chen, Yong-Xiang, Rusinova, Alexandra, Chandra, Anchal, Bierbaum, Martin, Gremer, Lothar, Triola, Gemma, Waldmann, Herbert +2 more·2011·Nature Chemical Biology

Abstract

Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDEδ is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDEδ. The structure explains the nucleotide-independent binding of Rheb to PDEδ and the relaxed specificity of PDEδ. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDEδ for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy.

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Crossref · 10.1038/nchembio.686

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Authors
Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., & Wittinghofer, A.
Affiliations
  • Max Planck Institute of Molecular Physiology (DE)
  • Max Planck Society (DE)
  • TU Dortmund University (DE)
Corresponding author
Wittinghofer, Alfred
Venue
Nature Chemical Biology
Published
2011-10-16
Volume
7
Issue
12
Pages
942-949
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
OpenAlex
W1979111896
Cited by
252
References
47
Citations by year
2026: 8 · 2025: 10 · 2024: 5 · 2023: 11 · 2022: 12 · 2021: 22 · 2020: 16 · 2019: 21 · 2018: 23 · 2017: 24 · 2016: 27 · 2015: 11 · 2014: 20 · 2013: 19 · 2012: 17
FWCI
7.91
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
ARL2, ARL3, guanine nucleotide dissociation inhibitor, Rheb, PDEδ, Rab GTPases, Rho GTPases, protein complex structure, anticancer drug targets
MeSH terms
Animals, Biological Transport, Cells, Cultured, Dogs, Guanosine Triphosphate, Humans, Models, Molecular, Protein Conformation, GTP-Binding Proteins, ADP-Ribosylation Factors, Cyclic Nucleotide Phosphodiesterases, Type 6, Prenylation

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