Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites

被引：36

作者：

Chen, Patty B. ^{[1
,2
,3
]}

Ding, Shuai ^{[1
,2
,3
]}

Zanghi, Gigliola ^{[4
]}

Soulard, Valerie ^{[4
]}

DiMaggio, Peter A. ^{[6
]}

Fuchter, Matthew J. ^{[7
]}

Mecheri, Salah ^{[1
,2
,3
]}

Mazier, Dominique ^{[4
,5
]}

Scherf, Artur ^{[1
,2
,3
]}

Malmquist, Nicholas A. ^{[1
,2
,3
]}

机构：

[1] Inst Pasteur, Dept Parasites & Insectes Vecteurs, Unite Biol Interact Hote Parasite, F-75015 Paris, France

[2] CNRS, ERL 9195, F-75015 Paris, France

[3] INSERM, UMR 1201, F-75015 Paris, France

[4] Univ Paris 06, Sorbonne Univ, Ctr Immunol & Malad Infect CIMI Paris, INSERM,U1135,CNRS,ERL 8255, 91 Bd Hop, F-75013 Paris, France

[5] Ctr Hosp Univ Pitie Salpetriere, AP HP, F-75013 Paris, France

[6] Univ London Imperial Coll Sci Technol & Med, Dept Chem Engn, South Kensington Campus, London SW7 2AZ, England

[7] Univ London Imperial Coll Sci Technol & Med, Dept Chem, South Kensington Campus, London SW7 2AZ, England

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

欧洲研究理事会; 英国工程与自然科学研究理事会;

关键词：

SUBSTRATE-SPECIFICITY; MALARIA PARASITES; HISTONE; H3; METHYLATION; DNA; INHIBITORS; EXPRESSION; MECHANISM; GENES;

D O I：

10.1038/srep21802

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epigenetic control via reversible histone methylation regulates transcriptional activation throughout the malaria parasite genome, controls the repression of multi-copy virulence gene families and determines sexual stage commitment. Plasmodium falciparum encodes ten predicted SET domain-containing protein methyltransferases, six of which have been shown to be refractory to knock-out in blood stage parasites. We have expressed and purified the first recombinant malaria methyltransferase in sufficient quantities to perform a full enzymatic characterization and reveal the ill-defined PfSET7 is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines 4 and 9. Steady-state kinetics of the PfSET7 enzyme are similar to previously characterized histone methyltransferase enzymes from other organisms, however, PfSET7 displays specific protein substrate preference towards nucleosomes with pre-existing histone H3 lysine 14 acetylation. Interestingly, PfSET7 localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stage parasites, and throughout the cytoplasm in salivary gland sporozoites. Characterized recombinant PfSET7 now allows for target based inhibitor discovery. Specific PfSET7 inhibitors can aid in further investigating the biological role of this specific methyltransferase in transmission, hepatic and blood stage parasites, and may ultimately lead to the development of suitable antimalarial drug candidates against this novel class of essential parasite enzymes.

引用

页数：14

共 52 条

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