p67 : a cryptic lysosomal hydrolase in trypanosoma brucei?
Abstract
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.
Citation
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
Publication
Parasitology
Status
Peer reviewed
ISSN
0031-1820Type
Journal article
Description
Funding: 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.Collections
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