Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes

Wu, Yao-Wen, Oesterlin, Lena K., Tan, Kui-Thong, Waldmann, Herbert, Alexandrov, Kirill and Goody, Roger S. (2010) Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes. Nature Chemical Biology, 6 7: 534-540. doi:10.1038/NCHEMBIO.386

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Author Wu, Yao-Wen
Oesterlin, Lena K.
Tan, Kui-Thong
Waldmann, Herbert
Alexandrov, Kirill
Goody, Roger S.
Title Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes
Journal name Nature Chemical Biology   Check publisher's open access policy
ISSN 1552-4450
1552-4469
Publication date 2010-07
Sub-type Article (original research)
DOI 10.1038/NCHEMBIO.386
Volume 6
Issue 7
Start page 534
End page 540
Total pages 7
Editor Terry L Shepherd
Philip Campbell
Place of publication New York, NY, U.S.A.
Publisher Nature Publishing Group
Collection year 2011
Language eng
Formatted abstract
Post-translationally isoprenylated proteins represent major hubs in most membrane-connected signaling networks. GDP dissociation inhibitors (GDIs) are molecular chaperones that shuttle geranylgeranylated GTPases between membranes and the cytosol. Despite numerous studies, the mechanism of targeted membrane delivery of GTPases remains unknown. Here we have combined chemical synthesis and expressed protein ligation to generate fluorescent lipidated RabGTPase-based sensor molecules. Using these protein probes, we have demonstrated that RabGDI and the related Rab escort protein REP show a three-order-of-magnitude greater affinity for GDP-bound Rab GTPase than for the GTP-bound state. Combined with a relatively high dissociation rate of the Rab–GDI complex, this would enable guanine nucleotide exchange factors (GEFs) to efficiently dissociate the complex and promote membrane attachment of the GTPase. The findings suggest strongly that GEFs are necessary and sufficient for membrane targeting of GTPases and that the previously proposed GDI displacement factors (GDFs) are not thermodynamically required for this process.
© 2010 Nature America, Inc.
Keyword GDP-dissociation inhibitor
Guanine-nucleotide exchange
Escort protein
Bound Rab
Complex
Displacement
Activation
Rabex-5
Geranylgeranyltransferase
Geranylgeranylation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Special issue: "Focus on Lipids".

 
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Created: Sun, 04 Jul 2010, 00:01:31 EST