Desmoplakin supplies a physical connection between junctional plaques and intermediate-filament networks. Human N-terminal plaque-partner experiments and C-terminal filament-binding evidence complement mouse loss/rescue experiments showing disruption of filament anchorage and junctional integrity. The integrated structural role also includes cytoplasmic assembly particles and cardiac fascia-adherens-like mixed junctions. These are nonexclusive functional pools, not evidence that every DSP molecule is soluble cytosol or an integral membrane protein. PMID:9348293(https://pubmed.ncbi.nlm.nih.gov/9348293/), PMID:29878302(https://pubmed.ncbi.nlm.nih.gov/29878302/), PMID:9864371(https://pubmed.ncbi.nlm.nih.gov/9864371/), PMID:15479741(https://pubmed.ncbi.nlm.nih.gov/15479741/), PMID:16406610(https://pubmed.ncbi.nlm.nih.gov/16406610/).
Human keratinocyte experiments establish a separable contribution to EB1-dependent connexin-43 targeting. DSP-N-terminal association with EB1, endogenous-cell assays and mutations that impair EB1 association while retaining other junctional properties support a spatial-organizing mechanism. This does not demonstrate direct DSP–microtubule binding or DSP motor activity. The more specific positive regulation of protein localization to cell-cell junction describes the measured endpoint. Mouse ninein recruitment and rat/mouse Cx43 turnover experiments corroborate recruitment and stabilization while retaining their organism and engineered-construct boundaries. PMID:25225338(https://pubmed.ncbi.nlm.nih.gov/25225338/), PMID:17227889(https://pubmed.ncbi.nlm.nih.gov/17227889/), PMID:29959233(https://pubmed.ncbi.nlm.nih.gov/29959233/).
The single core combines desmosome organization, intermediate-filament organization and positive regulation of junctional protein localization. Current typed ontology checks show these selected process terms are nonredundant. Broader existing organization, adhesion and localization assertions remain supported through this physical mechanism and its cellular context. Separate copies of the same structural activity, and new rows added only to mirror core slots, are unnecessary.
Three natural splice products have independently checked sequences: DPI, 2,871 residues; DPII, 2,272 residues, lacking canonical residues 1195–1793; and DSPIa, 2,428 residues, lacking 1351–1793. Both shorter products retain the terminal interaction regions and differ within the central rod. Shared sequence does not establish equivalent activity in every tissue. The 584-residue plaque construct and historical engineered DPII constructs are not automatically identical to any natural product without their own sequence proof.
Positive PKP1, PKP2, JUP, cadherin and EB1 interactions support informative binding classes, with fragment and cellular-complex assays distinguished. PKP2's cytoskeletal-component grounding is explicit: human Q99959 GO:0005882 ISS derives from mouse Q9CQ73; rat F1M7L9 ISO derives from MGI:1914701, the same mouse gene. Mouse IDA cites PMID:16917092. This is curator-supported component evidence, not independently recovered human/rat microscopy or a claim that PKP2 polymerizes intermediate filaments. The independently recovered human DSP-NTP/PKP2 binary experiment supplies the pair evidence. PMID:11790773(https://pubmed.ncbi.nlm.nih.gov/11790773/), PMID:16917092(https://pubmed.ncbi.nlm.nih.gov/16917092/).
Two independently verified FES associations support protein kinase binding under the exact term definition. The co-IP record uses human FLAG-tagged FES in the curated DLD-1 context; the separate AP-MS record uses N-terminal Strep/HA FES in HEK293 Flp-In T-REx cells and is spoke-expanded. The definition does not require purified reconstitution or catalytic-site recognition. Neither assay transfers FES kinase activity to DSP. PKC-alpha association remains a positive scaffold-dependent context; its imported bovine partner accession is retained rather than rewritten from the human host cell. PMID:25852190(https://pubmed.ncbi.nlm.nih.gov/25852190/), PMID:32707033(https://pubmed.ncbi.nlm.nih.gov/32707033/), PMID:18474624(https://pubmed.ncbi.nlm.nih.gov/18474624/).
DSP/COP9 and DSP/TRF2 associations remain positive contextual findings. The former includes DSP-dependent EGFR handling, but much of the differentiation/rescue work perturbs COPS3, and enzymatic deneddylation belongs to COP9. Nuclear fractionation, ChIP/FISH, perturbation and rescue support the latter context without purified DNA binding or an autonomous telomere enzyme. The proposed lamina mechanism remains unresolved. PMID:28891468(https://pubmed.ncbi.nlm.nih.gov/28891468/), PMID:31595153(https://pubmed.ncbi.nlm.nih.gov/31595153/).
The reproducible source extracts expose five target measurement records and 24 exact Reactome membership paths. The raw-source hashes, public URLs and parser distinguish original measured data from interpretation. RNA capture supplies DSP-positive crosslinked HeLa evidence. Human urinary and parotid fractions contain DSP peptides, and a genuine author-thesis annex linked to the sperm-nucleus study records three peptides with 2.1% coverage. These results are retained as contextual evidence; they are not dismissed as contamination or silently converted into isoform-specific functions. PMID:22658674(https://pubmed.ncbi.nlm.nih.gov/22658674/), PMID:19056867(https://pubmed.ncbi.nlm.nih.gov/19056867/), PMID:19199708(https://pubmed.ncbi.nlm.nih.gov/19199708/), PMID:21630459(https://pubmed.ncbi.nlm.nih.gov/21630459/), institutional thesis record.
The target-specific B-cell exosome table and neutrophil ficolin-rich granule table remain inaccessible. Independent positive fraction detections do not resolve those particular measurements. Current Reactome membership is retained as a model assertion with its precise chain; it is not substituted for an unread original target table. The HPA target HTML explicitly gives cell-junction-specific supported reliability in A-431; it does not itself resolve desmosomal ultrastructure. PMID:20458337(https://pubmed.ncbi.nlm.nih.gov/20458337/), PMID:23650620(https://pubmed.ncbi.nlm.nih.gov/23650620/), HPA DSP.
The human oral-epithelial envelope paper directly identifies DSP-derived material after resistant-envelope preparation and peptide sequencing. That supports incorporation. It does not recover a joined DSP cross-link peptide or demonstrate DSP catalyzing, templating or otherwise performing covalent cross-link formation. Accordingly the process assertion is over-scoped, while the envelope location and differentiation context remain positive. PMID:10908733(https://pubmed.ncbi.nlm.nih.gov/10908733/).
The S299R human family study establishes clinical cardiac and genetic observations. Its proposed phosphorylation/JUP mechanism does not measure a His-cell/Purkinje-cell interface, and clinical arrhythmia does not by itself establish ventricular-cell action-potential regulation. Those three specific assertions are marked over-annotated; broader cardiac conduction context is retained. This is a specificity judgment, not a claim that DSP has no electrical role or that patient measurements are false. PMID:12373648(https://pubmed.ncbi.nlm.nih.gov/12373648/).
All 126 imported annotation dictionaries, qualifiers, partners and original references are preserved. The final decisions are 62 ACCEPT, 35 KEEP_AS_NON_CORE, 21 MODIFY, four UNDECIDED and four MARK_AS_OVER_ANNOTATED; no NEW or REMOVE is proposed. PAINT node/descent and donor records were examined; target self-grounding is not circularity, and donor count is not a measure of inference strength. The four undecided cases concern source-specific access limitations, including COL17A1 interaction and the exact negative-differentiation assay.
Normal publication flags are retained byte-for-byte, including abstract-only caches for sources separately recovered through genuine original routes. A flag does not imply that Methods or Results were present or read. The source guide identifies the operative evidence routes and construct/species boundaries. Existing shared main caches are protected; the independently generated variants remain research records only. The configured Falcon attempt and fallback both failed with recorded authentication/quota errors; no provider report was fabricated. This manual source review is separate from those failed provider attempts.
Four short exact anchors occur once each in the review YAML: five words from PMID:9348293, eight from PMID:25225338, and six each from PMID:10908733 and PMID:12373648. This notes file and the source guide use paraphrase rather than repeating those excerpts. The generic envelope/clinical anchors identify assay scope; the operative reasoning rests on the independently read full originals, not those short phrases alone.
The project-specific ClinGen curation instruction retains supported generic protein-binding annotations as KEEP_AS_NON_CORE when no evidence-backed refinement is established. It intentionally takes precedence over the skill's general informational-exclusion recommendation. The COPS3 and TERF2 interactions remain positive and non-core; their revised reasons explain the partner-class limits without demanding purified catalytic-interface recognition. The general validator may continue to report these two policy advisories. An initial follow-up proposal missed this durable instruction and was corrected before candidate construction.
All 19 plasma-membrane assertions remain ACCEPT. The current definition includes associated proteins; it does not require insertion through the bilayer. Basolateral membrane cannot represent all observed epithelial, cardiac and other contexts, and an unspecified membrane region adds no demonstrated domain identity. Current is_a/part_of closure does not place desmosome or fascia adherens below plasma membrane, so the existing plasma-membrane pool is now represented explicitly alongside those locations in the same integrated core. The source-specific granule and inaccessible exosome uncertainties remain unchanged.
Neural-patterning rows 77/78 now distinguish regionalization from observed mouse neuroepithelial structural integrity. The source tuples remain unchanged. Newly recovered original text is located in the source guide; the cached abstract remains unchanged.
Three once-only anchors preserve the positive COPS3/TERF2 associations and the PKP2 head-domain conclusion. The authentic PMID:11790773 Figure 6 PKP1a comparison remains correctly attributed; it is not replaced with the separate mouse knockout paper PMID:9864371. Existing raw-derived measurement and Reactome-path files are now cited only for the records they reproduce. Their underlying sources, hashes and parser remain unchanged. The four earlier excerpts are preserved, with new totals of 9 words for PMID:28891468, 10 for PMID:31595153 and 13 for PMID:11790773. No new annotation or core unit is added.