p67 : a cryptic lysosomal hydrolase in trypanosoma brucei?
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p67 is a type I transmembrane glycoprotein of the terminal lysosome of African trypanosomes. Its biosynthesis involves transport of an initial gp100 ER precursor to the lysosome, followed by cleavage to N-terminal (gp32) and C-terminal (gp42) subunits that remain non-covalently associated. p67 knockdown is lethal, but the only overt phenotype is an enlarged lysosome (~250 nm to >1000 nm). Orthologues have been characterized in Dictyostelium and mammals. These have processing pathways similar to p67, and are thought to have phospholipase B-like (PLBL) activity. The mouse PLBD2 crystal structure revealed that the PLBLs represent a subgroup of the larger N-terminal Nucleophile (NTN) superfamily, all of which are hydrolases. NTNs activate by internal autocleavage mediated by a nucleophilic residue, i.e., Cys, Ser, or Thr, on the upstream peptide bond to form N-terminal α (gp32) and C-terminal β (gp42) subunits that remain non-covalently associated. The N-terminal residue of the β subunit is then catalytic in subsequent hydrolysis reactions. All PLBLs have a conserved Cys/Ser dipeptide at the α/β junction (Cys241/Ser242 in p67), mutation of which renders p67 non-functional in RNAi rescue assays. p67 orthologues are found in many clades of parasitic protozoa, thus p67 is the founding member of a group of hydrolases that likely play a role broadly in the pathogenesis of parasitic infections.
Koeller , C M , Smith , T K , Gulick , A M & Bangs , J D 2020 , ' p67 : a cryptic lysosomal hydrolase in trypanosoma brucei ? ' , Parasitology , vol. Accepted manuscipt . https://doi.org/10.1017/S003118202000195X
Copyright © The Author(s) 2020. Published by Cambridge University Press. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1017/S003118202000195X.
DescriptionFunding: This work was supported by United States Public Health Service Grants R01 AI056866 to JDB, and by support of the Jacobs School of Medicine and Biomedical Sciences.
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