A Molecular Analysis of the Aminopeptidase P-Related Domain of PID-5 from Caenorhabditis elegans

Anna Lloyd, Kyle Gregory, Elwyn Isaac, K. Ravi Acharya

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1 Citation (SciVal)


A novel protein, PID-5, has been shown to be a requirement for germline immortality and has recently been implicated in RNA-induced epigenetic silencing in the Caenorhabditis elegans embryo. Importantly, it has been shown to contain both an eTudor and aminopeptidase P-related domain. However, the silencing mechanism has not yet been fully characterised. In this study, bioinformatic tools were used to compare pre-existing aminopeptidase P molecular structures to the AlphaFold2-predicted aminopeptidase P-related domain of PID-5 (PID-5 APP-RD). Structural homology, metal composition, inhibitor-bonding interactions, and the potential for dimerisation were critically assessed through computational techniques, including structural superimposition and protein-ligand docking. Results from this research suggest that the metallopeptidase-like domain shares high structural homology with known aminopeptidase P enzymes and possesses the canonical ‘pita-bread fold’. However, the absence of conserved metal-coordinating residues indicates that only a single Zn2+ may be bound at the active site. The PID-5 APP-RD may form transient interactions with a known aminopeptidase P inhibitor and may therefore recognise substrates in a comparable way to the known structures. However, loss of key catalytic residues suggests the domain will be inactive. Further evidence suggests that heterodimerisation with C. elegans aminopeptidase P is feasible and therefore PID-5 is predicted to regulate proteolytic cleavage in the silencing pathway. PID-5 may interact with PID-2 to bring aminopeptidase P activity to the Z-granule, where it could influence WAGO-4 activity to ensure the balanced production of 22G-RNA signals for transgenerational silencing. Targeted experiments into APPs implicated in malaria and cancer are required in order to build upon the biological and therapeutic significance of this research.
Original languageEnglish
Article number1132
Number of pages23
Issue number7
Publication statusPublished - 14 Jul 2023

Bibliographical note

Funding: This research received no external funding.
Data Availability Statement: No new data created.


  • Caenorhabditis elegans
  • PID-5
  • RNA-induced epigenetic silencing
  • alphafold2
  • aminopeptidase P
  • bioinformatics
  • dimerisation
  • zinc metalloprotease

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry


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