DDHD1

Summary: The ancestral phospholipase inference is valid; target chemistry permits an A1 refinement.

Reason: The saved PAINT IBD places glycerophospholipase activity at the eukaryotic root PTN000397232, and the current PTHR23509 tree places human DDHD1 below that node in subfamily SF32. Fly, worm and yeast sources include experimental phospholipase annotations. This is a supported ancestral placement, not a pairwise donor-count argument. DDHD1 is characterized as an sn-1 glycerophospholipid hydrolase, so GO:0008970 specifies the chemistry more precisely. GO:0008970 is already represented by the existing RHEA/EC annotation; the refinement specifies the supported chemistry.

Proposed replacements: glycerophospholipid phospholipase A1 activity

Summary: The cited SEC24C pull-down tests SEC23IP/p125.

Reason: PMID:17428803 Methods specify FLAG-p125 and GST-human Sec24C; Results and Figure 7B assign the interaction to p125. The paper distinguishes p125 from PA-PLA1, and the official Q9Y6Y8 record identifies p125 as SEC23IP. These assay details support a source-to-target mismatch for this DDHD1 row. The PTHR23509 member table independently separates SEC23IP/Q9Y6Y8 (SF4) from DDHD1/Q8NEL9 (SF32).

Summary: The cited mouse Sec23A pull-down tests SEC23IP/p125.

Reason: PMID:17428803 Methods specify GST-mouse Sec23A and FLAG-p125, and Figure 7B reports that pair. Q01405 is mouse Sec23a; the official Q9Y6Y8 record identifies p125 as SEC23IP, distinct from DDHD1/PA-PLA1. This experimental source therefore supports a different target protein. The cached abstracts of PMID:17428803 and PMID:15623529 also distinguish p125 from PA-PLA1; the removal rests on the inspected assay Methods and Results, not on the paper title.

Summary: The verified isoform-2 interaction can be specified as DNA-binding transcription factor binding.

Reason: The HuRI record identifies Q8NEL9-2 with ZBTB24/O43167 in pooled, array and validated yeast two-hybrid stages. Both sequence/taxon ROGIDs match the stated current proteins; the DDHD1 construct corresponds to the 872-aa isoform. Human ZBTB24 binds a specific promoter motif and regulates target transcription in PMID:30085123, satisfying the partner definition of GO:0140297. This refinement records the physical partner class. The study does not establish a physiological transcriptional role for DDHD1 or transfer this result to its other products. These controlled Y2H stages demonstrate qualitative binding capacity, without establishing a native neuronal complex, quantitative affinity or the partner’s transcriptional mechanism in DDHD1.

Proposed replacements: DNA-binding transcription factor binding

Summary: Retain the verified isoform-2 interaction with CR1L as non-core.

Reason: HuRI records Q8NEL9-2 binding to CR1L/Q2VPA4 in pooled, array and validated yeast two-hybrid stages, with matching sequence/taxon ROGIDs. The assay concerns the full-length 569-aa CR1L construct in yeast; its signal sequence and mammalian processing/localization constrain physiological interpretation. Neither the assay nor the reviewed partner record establishes the signal-initiating receptor role required by GO:0005102. The receptor-like name alone does not justify that refinement. Preserve the positive interaction as non-core without inferring complement regulation by DDHD1. Retaining this supported generic interaction follows the user’s explicit CLINGEN_MENDELIAN project instruction; the repository-wide information-exclusion recommendation is not the policy applied to this project.

Summary: The valid broad ancestral location can be refined to the directly observed cytosol.

Reason: Cytoplasm is placed at PTN000397232 by an experimentally grounded PAINT IBD and inherited by human DDHD1 on the current tree. This broad placement is consistent with the target evidence. PMID:15623529 Figure 5B reports cytosolic localization of expressed human PA-PLA1 in Vero cells; Reactome also explicitly locates Q8NEL9 in cytosol. GO:0005829 is a part of cytoplasm and is the more informative location. The tagged-expression result does not establish equivalent localization for every encoded isoform. Cytosol is already represented by the existing Reactome annotation; the refinement specifies the observed compartment. This describes the cytosolic protein pool and does not establish freely soluble catalysis away from membrane interfaces or exclude transient access to mitochondrial-surface phospholipids.

Proposed replacements: cytosol

Summary: Refine the valid UniProt cytoplasm mapping to cytosol.

Reason: UniProt location SL-0086 genuinely maps to GO:0005737. Its cited source PMID:15623529 includes a human PA-PLA1 comparator despite the p125-focused title: the Methods describe a full-length 872-aa construct, and Figure 5B shows FLAG-PA-PLA1 in the cytosol of Vero cells. This supports the narrower cytosol term. The historical construct is not assigned to a modern isoform solely from its length, and the observation does not exclude context-dependent membrane association. Cytosol is already represented by the existing Reactome annotation; the refinement specifies the observed compartment.

Proposed replacements: cytosol

Summary: Accept the target-specific Reactome cytosol location.

Reason: Reactome R-HSA-6786650 places DDHD1 in the cytosol during phosphatidate hydrolysis. The human PA-PLA1 localization experiment in PMID:15623529 independently supports this compartment. The pathway grouping of DDHD1 and DDHD2 does not establish a physiological heterocomplex or identical localization of all alternative products. Entity-level locators are supplied in the source guide.

Summary: Accept the glycerophospholipid phospholipase A1 activity.

Reason: The composite electronic PLA1 annotation. The current term denotes hydrolysis at sn-1 of a diacyl glycerophospholipid to a 2-acyl lysophospholipid plus fatty acid. PMID:20359546 abstract explicitly reports purified recombinant DDHD1 converting PI to LPI and PA-dependent activity, and PMID:22922100 explicitly reports PA-PLA1/DDHD1 DDHD-domain mutation effects despite its DDHD2-focused title. Human WT versus S537A perturbation/rescue in PMID:24599962 provides independent human functional corroboration. The accessible abstracts do not identify every recombinant construct species or isoform, and the full 20359546/22922100 publisher text was inaccessible. Preserve all RHEA and EC source identifiers without converting every substrate mapping into a separately proven human activity.

Summary: Accept direct participation in phosphatidylinositol metabolism.

Reason: Phosphatidylinositol metabolic process: DDHD1 itself catalyzes PI deacylation to LPI, directly supported by the recombinant assay and cell-labeling results summarized in PMID:20359546. Retain the mechanistically supported broad process rather than infer a complete acyl-chain remodeling cycle; GO:0036149 specifically requires sequential deacylation/re-acylation and is not established by these assays. PMID:37189713 supplies supporting lipid-profile context only: mouse plasma PI increases and a one-patient human serum comparison do not establish individual substrate kinetics or a general clinical biomarker.

Summary: The DDHD-domain metal-binding mapping remains unresolved.

Reason: IPR004177 maps the DDHD domain to metal ion binding, but its official description presents the four conserved residues as a possible metal-binding site and says the domain function is unknown. PMID:22922100 DDHD-residue mutations establish functional importance to phospholipase activity, not metal occupancy, identity or binding stoichiometry. No target-specific direct binding evidence was recovered. Do not equate a necessary catalytic-domain residue with demonstrated metal binding or reject the mapping categorically.

Summary: Retain activity-dependent mitochondrial-fission regulation as non-core.

Reason: PMID:24599962 explicitly assays human FLAG-PA-PLA1/DDHD1 in HeLa cells. WT overexpression fragments mitochondria; two independent siRNAs elongate them and reduce CCCP-induced fragmentation; siRNA-resistant WT but not S537A rescues. These support activity-dependent positive regulation of mitochondrial fission, preserving the existing acts_upstream_of_or_within qualifier. This is a cell-context output of phospholipid metabolism, not an independent membrane-scission molecular function. MitoPLD/PA-probe experiments support a local PA model, but bulk mitochondrial PA/LPA and Drp1/Mfn distributions did not change. DDHD1 depletion did not produce the same phenotype in MEFs. Do not transfer mouse sperm phenotypes to human core biology.