Additional remarks phenotype | Mutant/mutation
The mutant expresses a mutated form of KIN, in which the T616, a conserved threonine residue in the activation loop, was replaced by aspartic acid.
Protein (function)
KIN is a putative serine/threonine kinase, with limited homology to the conserved family of sucrose non-fermenting 1 (SNF1) and AMP-activated kinases (AMPK) that regulate cellular energy homeostasis in yeast and mammalian cells, respectively. AMPK is a heterotrimeric complex comprising an α -catalytic subunit and two regulatory subunits β and γ. Although avian Plasmodium spp. genomes encode homologues to α, β and γ subunits, mammalian Plasmodium spp. seem to have lost the heterotrimeric complex and only retained KIN as a plausible AMPKα -related protein kinase. It is still possible that cryptic β and γ subunits exist but remain to be identified or that the poorly conserved N- and C-terminal extensions serve these functions. Homology of P. berghei and P. falciparum KIN to the AMPKα subunit is confined to the kinase domain, which includes a conserved threonine residue in the activation loop (T616 in P. berghei KIN), the phosphorylation of which is essential for SNF1 and AMPK activity, and replacement of this threonine by an aspartic acid residue has been validated as a phosphomimetic.
Phenotype
KIN(T616D) parasites generated fewer merozoites and lower parasitaemia in mice
Additional information
In this study they analysed blood stage/growth multiplication in mice kept under a dietary caloric restriction (CR) protocol (30–40% reduction in calorie intake, without changes in any dietary component, for 2–3 weeks before infection). Evidence is presented that KIN acts as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status.
Parasites lacking KIN (Δkin parasites) showed normal merozoite numbers in CR comparable to wild-type parasites in control experiments (normal diet), whereas wild type parasites produced fewer merozoites in CR. From day 4 onward, Δkin parasites outgrew wild-type in both dietary conditions, but presented lower parasitaemia in CR compared to AL mice, suggesting that additional parasite molecules may control growth at this point of infection.
See also mutant RMgm-521 lacking expression of KIN: this mutant showed a phenotype in salivary gland sporozoite production.
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