Structure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase

Loïc Carrique, Lionel Ballut, Arpit Shukla, Neelakshi Varma, Resmi Ravi, Sébastien Violot, Bharath Srinivasan, Umesh Tippagondanahalli Ganeshappa, Sonia Kulkarni, Hemalatha Balaram () and Nushin Aghajari ()
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Loïc Carrique: UMR5086 CNRS-University of Lyon
Lionel Ballut: UMR5086 CNRS-University of Lyon
Arpit Shukla: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Neelakshi Varma: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Resmi Ravi: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Sébastien Violot: UMR5086 CNRS-University of Lyon
Bharath Srinivasan: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Umesh Tippagondanahalli Ganeshappa: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Sonia Kulkarni: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Hemalatha Balaram: Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Nushin Aghajari: UMR5086 CNRS-University of Lyon

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Plasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite. Purine nucleotide levels are regulated by anabolic processes and by nucleotidases that hydrolyse these metabolites into nucleosides. Certain apicomplexan parasites, including Pf, have an IMP-specific-nucleotidase 1 (ISN1). Here we show, by comprehensive substrate screening, that PfISN1 catalyzes the dephosphorylation of inosine monophosphate (IMP) and is allosterically activated by ATP. Crystal structures of tetrameric PfISN1 reveal complex rearrangements of domain organization tightly associated with catalysis. Immunofluorescence microscopy and expression of GFP-fused protein indicate cytosolic localization of PfISN1 and expression in asexual and gametocyte stages of the parasite. With earlier evidence on isn1 upregulation in female gametocytes, the structures reported in this study may contribute to initiate the design for possible transmission-blocking agents.

Date: 2020
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DOI: 10.1038/s41467-020-17013-x

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