Affinage · Plasmodium

DHHC2

PF3D7_0609800 · palmitoyltransferase DHHC2, putative

Annotated
2026-09-07
4 papers in source corpus 4 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DHHC2 (PF3D7_0609800) is an inner membrane complex (IMC)-resident palmitoyl-S-acyltransferase of the DHHC-CRD family that anchors substrate proteins to the IMC and is essential for cytoskeletal organization during parasite development (PMID:23638681, PMID:32395856). It first establishes its own IMC residence through PAT-dependent self-palmitoylation at its C-terminal cysteines (PMID:32395856), and then palmitoylates the N-terminal cysteines of IMC substrates to control their localization: in P. falciparum it modifies ISP1 and ISP3 (PMID:32395856), and in P. yoelii it acts as the major schizont IMC palmitoyl-acyltransferase modifying CDPK1 and GAP45 (PMID:35775739). The palmitoylated ISP1/ISP3 tether the IMC to subpellicular microtubules via β-tubulin, placing DHHC2 activity upstream of IMC–microtubule cytoskeletal integrity (PMID:32395856). Loss of DHHC2 function blocks zygote-to-ookinete differentiation and mosquito transmission in P. berghei (PMID:26526684) and causes defective schizont segmentation and growth arrest in P. yoelii (PMID:35775739), establishing DHHC2 as indispensable across both sexual and asexual stages. Enzymatic detail beyond this palmitoylation cascade and its structural basis has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2013 Low

    Placing DHHC2 within the apicomplexan DHHC-CRD palmitoyltransferase repertoire established it as a candidate enzyme in a parasite protein-acylation system, framing the question of whether it is essential and where it acts.

    Evidence Comparative genomic cataloguing of the DHHC-CRD family with localization and essentiality assessment across T. gondii and P. berghei

    PMID:23638681

    Open questions at the time
    • Catalog-level assignment only; no DHHC2-specific mechanistic or localization data for P. falciparum in this analysis
    • Substrates and catalytic activity of DHHC2 itself not tested
    • No phenotype attributed specifically to DHHC2
  2. 2015 Medium

    Conditional knockdown resolved whether DHHC2 has a non-redundant biological role by showing it is essential for post-fertilisation development, defining its requirement in transmission rather than early gamete biology.

    Evidence Promoter-swap conditional knockdown in P. berghei with life-cycle phenotyping and palmitoylation inhibitor studies

    PMID:26526684

    Open questions at the time
    • Molecular substrates of DHHC2 not identified in this study
    • Subcellular localization of DHHC2 not resolved
    • Single lab; mechanism linking loss of enzyme to ookinete block undefined
  3. 2020 High

    Direct enzyme–substrate work established DHHC2 as an IMC-localized PAT that both self-palmitoylates to secure its own IMC residence and palmitoylates ISP1/ISP3 to anchor them, identifying the first PAT–substrate pairs in malaria parasites and linking the enzyme to IMC–microtubule cytoskeletal integrity via β-tubulin.

    Evidence Conditional loss-of-function, fractionation and live imaging, in-parasite palmitoylation assays, cysteine mutagenesis, and Co-IP of ISP1/ISP3 with β-tubulin in P. falciparum

    PMID:32395856

    Open questions at the time
    • Structural basis of substrate cysteine recognition not determined
    • Whether DHHC2 self-palmitoylation is intramolecular or trans not resolved
    • Direct DHHC2 interaction with β-tubulin not tested (interaction shown for ISP1/ISP3)
  4. 2022 High

    Proteomic and genetic dissection in asexual stages showed DHHC2 is the major schizont IMC palmitoyl-acyltransferase and extended its substrate set to CDPK1 and GAP45, establishing its requirement for schizont segmentation and blood-stage growth beyond the sexual stage role.

    Evidence TurboID proximity-labeling IMC proteomics, conditional DHHC2 depletion with in vitro and in vivo growth assays, and palmitoylation assays for CDPK1 and GAP45 in P. yoelii

    PMID:35775739

    Open questions at the time
    • Full substrate repertoire in asexual stages not exhaustively defined
    • Mechanistic link between substrate palmitoylation and segmentation failure not fully dissected
    • Whether CDPK1/GAP45 palmitoylation by DHHC2 holds in P. falciparum not tested here

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of DHHC2 catalysis, its complete substrate repertoire across life-cycle stages, and the mechanism coupling substrate palmitoylation to cytoskeletal and segmentation defects remain open.
  • No structure or catalytic mechanism reported
  • Substrate recognition determinants undefined
  • Regulation of DHHC2 activity across stages unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
CDPK1 (PALMITOYLATION SUBSTRATE)GAP45 (PALMITOYLATION SUBSTRATE)ISP1 (PALMITOYLATION SUBSTRATE)ISP3 (PALMITOYLATION SUBSTRATE)

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 DHHC2 (PF3D7_0609800) is a member of the DHHC-CRD palmitoyl-S-acyl-transferase (PAT) family in Plasmodium falciparum; comprehensive analysis of the PAT repertoire in apicomplexans placed DHHC2 within this enzyme family, and some apicomplexan-specific DHHC members were shown to be essential for parasite growth with localization to parasite-specific organelles. Comparative genomic analysis of DHHC-CRD family combined with localization and essentiality assessment across Toxoplasma gondii and Plasmodium berghei Traffic (Copenhagen, Denmark) Low 23638681
2015 DHHC2 (PF3D7_0609800) is an essential palmitoyl-S-acyltransferase required for ookinete morphogenesis and malaria transmission in P. berghei; promoter-swap conditional knockdown that maintained DHHC2 expression in asexual blood stages but down-regulated it in sexual stages caused a complete block in post-fertilisation development and ookinete formation, while gamete formation, fertilisation, and DNA replication to tetraploid cells were normal. Promoter-swap conditional knockdown (loss-of-function) with phenotypic readout of life-cycle progression; palmitoylation inhibitor studies Scientific reports Medium 26526684
2020 DHHC2 (PF3D7_0609800) localizes to the inner membrane complex (IMC) and catalyses palmitoylation of N-terminal cysteines of IMC proteins ISP1 and ISP3, which controls their IMC localization and is required for zygote-to-ookinete differentiation; DHHC2 also undergoes autophosphorylation-independent self-palmitoylation at its own C-terminal cysteines via its PAT activity, which is necessary for its own IMC localization after zygote formation. Genetic knockdown/conditional loss-of-function, subcellular fractionation and live imaging for localization, palmitoylation assays, mutagenesis of cysteine residues (N-terminal cysteines of ISP1/ISP3 and C-terminal cysteines of DHHC2) The EMBO journal High 32395856
2020 IMC-anchored ISP1 and ISP3, whose palmitoylation is catalysed by DHHC2 (PF3D7_0609800), interact with microtubule component β-tubulin and serve as tethers to maintain the proper structure of subpellicular microtubules (SPMs) during zygote elongation, placing DHHC2 activity upstream of IMC-SPM cytoskeletal integrity. Co-immunoprecipitation (ISP1/ISP3 with β-tubulin), genetic loss-of-function, live imaging of cytoskeletal structure The EMBO journal Medium 32395856
2022 DHHC2 (PF3D7_0609800) is the major resident palmitoyl-acyltransferase of the schizont IMC in Plasmodium yoelii; depletion of DHHC2 caused defective schizont segmentation and growth arrest both in vitro and in vivo, and DHHC2 was shown to palmitoylate IMC proteins CDPK1 and GAP45 to control their IMC localization. TurboID proximity labeling proteomics to compile IMC proteome, conditional DHHC2 depletion (loss-of-function) with in vitro and in vivo growth assays, palmitoylation assays for CDPK1 and GAP45 substrates eLife High 35775739

Source papers

Stage 0 corpus · 4 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion. Traffic (Copenhagen, Denmark) 62 23638681
2020 A protein palmitoylation cascade regulates microtubule cytoskeleton integrity in Plasmodium. The EMBO journal 42 32395856
2015 The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission. Scientific reports 38 26526684
2022 Inner membrane complex proteomics reveals a palmitoylation regulation critical for intraerythrocytic development of malaria parasite. eLife 20 35775739