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Comparative analysis of apicoplast-targeted proteins in Toxoplasma gondii and other Apicomplexa species Natalie V. Kobets, Dmitrii B. Goncharov,
N.F.Gamaleya Research Institute of Epidemiology and Microbiology, nkobets2000@yahoo.com

Alexandr V. Seliverstov, Oleg A. Zverkov
Institute for Information Transmission Problems RAS (Kharkevich Institute), O.Zverkov@gmail.com

Toxoplasma gondii is an important medical and veterinary Apicomplexa pathogen and induces cerebral toxoplasmosis, highly common cause of morbidity in HIV patients. It was reported earlier that T. gondii apicoplast is involved in pathogen stage conversion and proliferation; however the role of different apicoplast proteins involved in these processes was not established. Elucidation of molecular mechanisms underlying the role of apicoplast in control of parasite proliferation is highly desirable for development of novel therapeutics that control infection and reactivation of this parasite. In this study we have analyzed nucleus encoded proteins with either confirmed or anticipated apicoplast-targeting like for housekeeping proteins: bacterial type RNA polymerase sigma subunit (RpoD), DNA ligase, cysteinyl-tRNA synthetase (CysRS), cell-cycle-associated protein kinase PRP4, enzymes IspA, IspB, IspE, IspF, IspG (GpcE), and IspH (LytB) of the mevalonate-independent pathway for isoprenoid biosynthesis, sulphur mobilisation protein SufC for an iron-sulphur cluster biogenesis pathway, enzymes LipA and LipB for lipoic acid biosynthesis. These proteins are encoded in nuclei of T. gondii or related species such as Eimeria tenella, Neospora caninum and Plasmodium spp. GpcE, LytB, and LipA proteins contain iron-sulphur clusters. SufC (with SufB, encoded in apicoplast) is necessary for ironsulphur cluster biogenesis. These proteins in T. gondii have extended N-terminus compared to other Apicomplexa species and no N-terminal signal peptide typical for Plasmodium spp apicoplast-targeted proteins [1-4]. N-terminus in T. gondii apicoplast-targeted proteins can be extended from 40 aa (LipB) and up to 408 aa (DNA ligase). Conservative domains, common for Apicomplexa and cyanobacterium Synechocystis sp. PCC 6803 proteins are located at C-


terminus. Significant additional extension of T. gondii proteins N-terminus possibly suggests that these proteins need processing. Significant N-terminus extension was also found for T. gondii protein kinase (ToxoDB:TGME49_209050) and some other proteins with no established connection to apicoplast. In contrast, rhoptry proteins secreted in response to pathogen-host interaction don't have additional N-terminus is even extension. 12 aa For example than T. P. gondii vivax ROP22 protein (ToxoDB:TGME49_207700) (PlasmoDB:PVX_111320). The unique features of T. gondii apicoplast proteins structure described above can be exploited for either genetic or drug-induced manipulations that may help to elucidate the role of these proteins in vital stages of pathogen development and control of its proliferation. T. gondii, N. caninum and E. tenella proteins are available from ToxoDB database, release 8.0; Plasmodium spp. proteins ­ from PlasmoDB database, release 9.2. This research is partly funded by the Ministry of education and science of Russia (grants 8481 and 8858). 1. K.E. Jackson et al. (2012) Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum // Int J Parasitol, 42:177­186. 2. B. Kumar et al. (2011) Interaction between sulphur mobilisation proteins SufB and SufC: evidence for an iron-sulphur cluster biogenesis pathway in the apicoplast of Plasmodium falciparum // Int J Parasitol, 41(9):991­999. 3. J. Mazumdar et al. (2006) Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii // PNAS, 103(35):13192­13197. 4. N. Thomsen-Zieger et al. (2003) Apicomplexan parasites contain a single lipoic acid synthase located in the plastid // FEBS Letters, 547:80­86. shorter