7t3v
Metal dependent activation of Plasmodium falciparum M17 aminopeptidase, spacegroup P22121 after crystals soaked with Zn2+
Structural highlights
FunctionAMPL_PLAF7 Aminopeptidase which preferentially cleaves leucine residues from the N-terminus of peptides (PubMed:17107951, PubMed:21844374, PubMed:22359643, PubMed:33536500, PubMed:34133730). Also, has some activity towards tryptophan and methionine and to a lesser extent towards phenylalanine (PubMed:17107951, PubMed:22359643, PubMed:34133730). Has very low activity or no activity towards the other amino acids (PubMed:17107951, PubMed:22359643, PubMed:34133730). In addition, cleaves the Cys-Gly dipeptide, probably as part of the glutathione regulation pathway; cleavage only occurs in the presence of Mn(2+) (PubMed:33303633). During the asexual blood stage, plays a role in the final step of host hemoglobin catabolism, by cleaving hemoglobin-derived oligopeptides providing a source of amino acids for the parasite protein synthesis and for the maintenance of osmotic homeostasis (PubMed:34133730). During the asexual blood stage, may also play a role during the ring-trophozoite transition (PubMed:21844374).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe metal-dependent M17 aminopeptidases are conserved throughout all kingdoms of life. This large enzyme family is characterized by a conserved binuclear metal center and a distinctive homohexameric arrangement. Recently, we showed that hexamer formation in Plasmodium M17 aminopeptidases was controlled by the metal ion environment, although the functional necessity for hexamer formation is still unclear. To further understand the mechanistic role of the hexameric assembly, here we undertook an investigation of the structure and dynamics of the M17 aminopeptidase from Plasmodium falciparum, PfA-M17. We describe a novel structure of PfA-M17, which shows that the active sites of each trimer are linked by a dynamic loop, and loop movement is coupled with a drastic rearrangement of the binuclear metal center and substrate-binding pocket, rendering the protein inactive. Molecular dynamics simulations and biochemical analyses of PfA-M17 variants demonstrated that this rearrangement is inherent to PfA-M17, and that the transition between the active and inactive states is metal dependent and part of a dynamic regulatory mechanism. Key to the mechanism is a remodeling of the binuclear metal center, which occurs in response to a signal from the neighboring active site and serves to moderate the rate of proteolysis under different environmental conditions. In conclusion, this work identifies a precise mechanism by which oligomerization contributes to PfA-M17 function. Furthermore, it describes a novel role for metal cofactors in the regulation of enzymes, with implications for the wide range of metalloenzymes that operate via a two-metal ion catalytic center, including DNA processing enzymes and metalloproteases. A metal ion-dependent conformational switch modulates activity of the Plasmodium M17 aminopeptidase.,Webb CT, Yang W, Riley BT, Hayes BK, Sivaraman KK, Malcolm TR, Harrop S, Atkinson SC, Kass I, Buckle AM, Drinkwater N, McGowan S J Biol Chem. 2022 Jul;298(7):102119. doi: 10.1016/j.jbc.2022.102119. Epub 2022 , Jun 9. PMID:35691342[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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