Title

Evidence for prenylation-dependent targeting of a Ykt6 SNARE in Plasmodium falciparum

Authors

Authors

L. Ayong; T. DaSilva; J. Mauser; C. M. Allen;D. Chakrabarti

Comments

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Abbreviated Journal Title

Mol. Biochem. Parasitol.

Keywords

Plasmodium falciparum; SNARE; Protein trafficking; Ykt6; Prenylation; TAIL-ANCHORED PROTEINS; RETICULUM-GOLGI TRANSPORT; MEMBRANE-FUSION; FARNESYLTRANSFERASE INHIBITORS; INFECTED ERYTHROCYTES; TRAFFICKING; RAS; GERANYLGERANYLTRANSFERASE; LOCALIZATION; PARASITES; Biochemistry & Molecular Biology; Parasitology

Abstract

Ykt6 proteins are the most versatile fusogens in eukaryotic cells, and the only SNAREs that can be both prenylated and acylated at a C-terminal CAAX motif. Unlike yeast and mammalian cells where a single Ykt6 gene is expressed, the Plasmodium falciparum genome encodes two Ykt6 proteins. We have investigated the expression and prenylation of the Ykt6 orthologue, PfYkt6.1 in intra-erythrocytic stages of P. falciparum. PfYkt6.1 localized to the parasite Golgi and other unidentified cytoplasmic compartments, and was partly cytosolic (similar to 50% in early trophozoites). The membrane-association of PfYkt6.1 was dependent on the presence of a conserved C-terminal CAAX motif (CCSIM). By expressing full-length and mutant proteins in Escherichia coli, we have shown that PfYkt6.1 indeed serves as substrate for prenylation by P. falciparum farnesyltransferases. Surprisingly, PfYkt6.1 could also be geranylgeranylated by parasite extracts independent of the C-terminal amino acid residue. Deletion of the CAAX motif inhibited both farnesylation and geranylgeranylation activities. Additionally, the PfYkt6.1 heptapeptide KQCCSIM, corresponding to the C-terminal CAAX sequence, inhibited the parasite farnesyltransferase activity with an IC(50) of 1 mu M. Our findings underscore the importance of CAAX motif-derived peptidomimetics for antimalarial drug development. (C) 2010 Elsevier B.V. All rights reserved.

Journal Title

Molecular and Biochemical Parasitology

Volume

175

Issue/Number

2

Publication Date

1-1-2011

Document Type

Article

Language

English

First Page

162

Last Page

168

WOS Identifier

WOS:000286556100009

ISSN

0166-6851

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