Structure of doubly prenylated Ypt1:GDI complex and the mechanism of GDI-mediated Rab recycling

Pylypenko, Olena; Rak, Alexey; Durek, Thomas; Kushnir, Susanna; Dursina, Beatrice; Thomae, Nicolas H; Constantinescu, Alexandru Tudor; Brunsveld, Luc; Watzke, Anja; Waldmann, Herbert; Goody, Roger S.; Alexandrov, Kirill

doi:10.1038/sj.emboj.7600921

Cited by 106 publications

(122 citation statements)

References 40 publications

(45 reference statements)

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“…The two related Rab molecular chaperones REP and GDI have similar structural organization, and their Rab binding interface is well conserved (5,10,11). This finding is consistent with the common function of REP/GDI (i.e.…”

supporting

confidence: 78%

A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism

Ignatev

Кравченко²,

Rak³

et al. 2008

Journal of Biological Chemistry

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supporting

confidence: 78%

A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism

Ignatev

Кравченко²,

Rak³

et al. 2008

Journal of Biological Chemistry

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“…One possibility is that the aliphatic tail fits into a pocket or interferes with an enzymatic process that is specific to RabGGTase but not to GGTase-I. The significance of lipidbinding pockets of REP for the RabGGTase reaction has been suggested (18,43). Further characterization of our GGTI and RabGGTI should lead to increased understanding of the possible differences and similarities in the active sites of the two enzymes.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Protein Geranylgeranyltransferase I and Rab Geranylgeranyltransferase Identified from a Library of Allenoate-derived Compounds

Watanabe

Fiji

Guo

et al. 2008

Journal of Biological Chemistry

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Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G 1 cell cycle arrest and induction of p21 CIP1/WAF1 . We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation.

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“…APT1, DHHC9 and GCP16 may be involved in palmitoylation on the Golgi. Model for extraction of prenylated Rab proteins from membranes via GDI, as previously formulated 87 . (1) The initial recognition occurs via the low-affinity interaction of the Rab protein with the C-terminal-binding region (CBR) of GDI.…”

Section: Discussionmentioning

confidence: 99%

“…4) 87 . In short, GDI recognizes the GDP-bound form of Rab through an initial interaction that involves only the globular part of the GTPase.…”

Section: Membrane Extraction and Delivery Of Prenylated Proteins Of Tmentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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Structure of doubly prenylated Ypt1:GDI complex and the mechanism of GDI-mediated Rab recycling

Cited by 106 publications

References 40 publications

A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism

A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism

Inhibitors of Protein Geranylgeranyltransferase I and Rab Geranylgeranyltransferase Identified from a Library of Allenoate-derived Compounds

Therapeutic intervention based on protein prenylation and associated modifications

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