PMII (plasmepsin II, PF3D7_1408000, Q8I6V3) - curation notes

Note: Automated deep research was unavailable in this environment (Falcon auth failure,
invalid OpenAI key). These notes are a manual literature review based on the UniProt record,
the cached publications in publications/, and targeted web searches for key primary papers.

Identity and family

• Plasmepsin II, pepsin-family (MEROPS A01.023) aspartic protease of Plasmodium falciparum 3D7,
  EC 3.4.23.39. 453 aa precursor; propeptide 1-124 containing the transmembrane anchor; mature
  chain 125-453 (UniProt).
• One of four food-vacuole plasmepsins (PMI, PMII, PMIV, HAP) encoded in a tandem cluster on
  chromosome 14, products of recent gene duplication
  PMID:11782538
  PMID:11782538

Molecular function: aspartic endopeptidase, hemoglobinase

• PMI and PMII initiate hemoglobin degradation by cleaving native Hb in the hinge region
  PMID:11782538.
• Gluzman et al. 1994 isolated vacuolar proteases; the second aspartic protease (later named PMII)
  PMID:8163662
  (abstract only; the identity of this enzyme as PMII is from later literature).
• Recombinant mature PMII degrades hemoglobin and a fluorogenic peptide, and is inhibited by pepstatin A
  PMID:29943906
  PMID:29943906
• PMII acts synergistically with HAP and PMIV on native hemoglobin
  PMID:11782538
• Zymogen structure: prosegment holds the domains apart rather than occluding the active site
  PMID:9886289

Localization and trafficking

• Food vacuole by IF and immunoEM
  PMID:11782538
• Type II integral membrane proenzyme; trafficked through the ER to cytostomal vacuoles, then with
  hemoglobin to the food vacuole where it is cleaved to soluble mature enzyme
  PMID:14709539
  PMID:14709539
  PMID:14709539
• With ALLN (blocks maturation), proPMII-GFP accumulates in the food vacuole membrane
  PMID:14709539
• So: active enzyme = food vacuole lumen; membrane-bound forms (ER, cytostomal vacuole membrane,
  food vacuole membrane) are biosynthetic/trafficking intermediates.
• The food vacuole (GO:0020020) is a lysosome-like organelle; in GO, food vacuole is_a phagolysosome
  is_a lysosome (checked via OLS), so the IBA "lysosome" is a correct but general location.
  PMID:14709539

Activation

• Proplasmepsin maturation is mainly by falcipains, with autoprocessing as backup
  PMID:18308731

Complex

• Part of a ~200 kDa hemozoin formation complex (HFC) in the food vacuole with falcipain 2/2',
  PMIV, HAP, HDP
  PMID:23471987
• No GO CC term exists for this complex (none in GOA for PMII). Not proposed as new term here; the
  complex has only co-IP/co-elution support.

Genetics / redundancy

• PMII knockout viable, modestly slower growth; substantial redundancy among FV plasmepsins
  PMID:15513918
  PMID:15513918
• In Dd2 background, PMII double knockouts grew normally; only Δpm4 reduced hemozoin
  PMID:17207486

Curation thoughts

• MF GO:0004190 aspartic-type endopeptidase activity: experimentally solid; core.
• BP hemoglobin catabolic process (GO:0042540): PMII catalyses hemoglobin cleavage steps itself;
  core. Host hemoglobin is endocytosed and catabolised inside the parasite food vacuole, so the
  plain (non-host-interaction) catabolic process term is appropriate.
• BP proteolysis: true but general; refine to hemoglobin catabolic process (not an is_a
  descendant of proteolysis in GO - it sits under protein catabolic process - but it is the
  informative process the proteolysis serves).
• CC: food vacuole and vacuolar lumen = site of action; vacuolar membrane, membrane and cytostome =
  zymogen trafficking intermediates (non-core). Lysosome IBA -> refine to food vacuole.
• Possible in vitro activity on erythrocyte membrane skeleton proteins at neutral pH has been
  reported in the literature (not cached, not used).