Article
- The EMBO Journal (2008) 27, 2444 - 2456
- doi:10.1038/emboj.2008.164
Published online: 28 August 2008
Subject Categories:
Structures of RabGGTase–substrate/product complexes provide insights into the evolution of protein prenylation
Zhong Guo1,a, Yao-Wen Wu1,a, Debapratim Das2, Christine Delon1, Janinna Cramer1, Shen Yu1, Sandra Thuns1, Nataliya Lupilova1, Herbert Waldmann2, Luc Brunsveld2, Roger S Goody1, Kirill Alexandrov1,3 and Wulf Blankenfeldt1
- Department of Physical Biochemistry, Max-Planck-Institute for Molecular Physiology, Dortmund, Germany
- Department of Chemical Biology, Max-Planck-Institute for Molecular Physiology, Dortmund, Germany
- Department of Molecular Cell Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
Correspondence to:
Kirill Alexandrov, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, St Lucia, 4072, Australia. Tel.: +61 7 3346 2110; Fax: +61 7 3346 2101; E-mail: k.alexandrov@imb.uq.edu.au
aThese authors contributed equally to this work
Received 29 April 2008; Accepted 28 July 2008
Abstract
Post-translational isoprenylation of proteins is carried out by three related enzymes: farnesyltransferase, geranylgeranyl transferase-I, and Rab geranylgeranyl transferase (RabGGTase). Despite the fact that the last one is responsible for the largest number of individual protein prenylation events in the cell, no structural information is available on its interaction with substrates and products. Here, we present structural and biophysical analyses of RabGGTase in complex with phosphoisoprenoids as well as with the prenylated peptides that mimic the C terminus of Rab7 GTPase. The data demonstrate that, unlike other protein prenyl transferases, both RabGGTase and its substrate RabGTPases completely 'outsource' their specificity for each other to an accessory subunit, the Rab escort protein (REP). REP mediates the placement of the C terminus of RabGTPase into the active site of RabGGTase through a series protein–protein interactions of decreasing strength and selectivity. This arrangement enables RabGGTase to prenylate any cysteine-containing sequence. On the basis of our structural and thermodynamic data, we propose that RabGGTase has evolved from a GGTase-I-like molecule that 'learned' to interact with a recycling factor (GDI) that, in turn, eventually gave rise to REP.
Keywords:
- protein prenylation,
- RabGTPases,
- Rab geranylgeranyl transferase,
- Rab escort protein
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