BBS4 (Q96RK4) curation notes

Identity / structure

• Human BBS4, 519 aa, UniProt Q96RK4; HGNC:969; gene on chr 15.
• TPR (tetratricopeptide-repeat) superhelical protein: UniProt annotates 10 TPR repeats (positions ~67–408); InterPro IPR011990/IPR019734; PANTHER PTHR44186:SF1 (BBS4). Belongs to the BBS4 family.
• Resolved in cryo-EM structure of the BBSome (PDB 6XT9, chain D). TCDB 3.A.33.1.1 "BBSome complex family"; ComplexPortal CPX-1908 BBSome.
• Disordered N-term (1–25) and C-term (440–519). REGION 1..66 and 338..519 "required for localization to centrosomes"; REGION 101..337 "Interaction with PCM1" [UniProt FT, ECO:0000269|PubMed:15107855].
• 3 isoforms; isoform 3 lacks aa 1–172 (loses N-terminal half incl. several TPRs).

Core biology

BBS4 is a core subunit of the BBSome (8-subunit complex: BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9, BBIP1/BBIP10). The BBSome is a coat-like cargo adaptor that sorts membrane proteins into/out of the primary cilium via IFT, working with the small GTPase ARL6/BBS3 and Rabin8/Rab8.

• BBSome composition + function + ciliary membrane localization: PMID:17574030. This paper IDed BBSome by MS and assigned subcellular location (centriolar satellites + ciliary membrane). It is the source for alpha-/beta-tubulin binding IDA annotations and BBSome part_of IDA.
• BBSome assembly order — BBS4 is added LAST onto the BBS7-BBS2-BBS9 core, after BBS1/BBS5/BBS8: PMID:22500027. Chaperonin BBS6/10/12 + CCT/TRiC required for assembly PMID:20080638.

BBS4-specific functions (the adaptor/PCM1 role)

• BBS4 as dynein/p150glued adaptor recruiting PCM1 to centriolar satellites: PMID:15107855. Source of: protein-macromolecule adaptor activity (IMP), dynactin binding (IDA), microtubule anchoring at centrosome (IMP), PCM1/DCTN1 interaction, centriolar satellite/PCM/centriole/basal body localization, cell-cycle/cytokinesis phenotypes (centrosome cycle IMP, mitotic cytokinesis IMP, regulation of cytokinesis IMP, protein localization to centrosome IMP).
• NOTE: the cytokinesis/cell-division-arrest/apoptosis effects are downstream secondary consequences of PCM1 mislocalization and MT de-anchoring on RNAi; these are over-annotations of the molecular role rather than direct BBS4 functions.
• DISC1 + BBS4 cooperatively recruit PCM1 (and ninein) to the centrosome; relevant to corticogenesis/neuronal migration: PMID:18762586. Source of centrosome IDA (PMID:18762586) and protein binding IPI.
• AZI1/CEP131 (centriolar satellite protein) interacts with BBSome via BBS4 and negatively regulates BBSome ciliary trafficking: PMID:24550735. Source of BBSome part_of IDA, centrosome IDA, cilium IDA, centriolar satellite IDA, protein binding IPI (PMID:24550735).
• BBIP10/BBIP1 is a BBSome subunit; BBSome functions in membrane trafficking to/inside primary cilium; BBIP10 (not BBS4) couples MT acetylation: PMID:19081074. Source of BBSome IPI, ciliary membrane IDA, cilium assembly NAS (PMID:19081074). The microtubule-stability/acetylation function in the title belongs to BBIP10, not BBS4.
• CEP290 interaction; BBS4 modifies CEP290 ciliopathy expression: [PMID:23943788 full text available]. Source of cilium IDA, centriolar satellite IDA, ciliary transition zone IDA, protein localization to cilium IMP, protein binding IPI.
• NPHP5/CEP290 regulate BBSome integrity & cargo delivery PMID:25552655 — protein binding IPI.
• BBS1/BBS3 regulate ciliary trafficking of PKD1; BBS4 interacts with PKD1 PMID:24939912 — protein binding IPI.

Transcriptional regulation claim

• PMID:22302990. Primarily a BBS7 study; "RNA polymerase II-specific DNA-binding transcription factor binding" IPI (MGI) for BBS4 rests on weak generalization. The nucleus IEA (GOC inter-ontology) and transcription-factor-binding IPI are poorly supported as a core function. Treat as non-core/uncertain.

Other annotations

• Many ISS (GO_REF:0000024) developmental/neurological/sensory process terms transferred from mouse ortholog (Q8C1Z7): heart looping, neural tube closure, retina homeostasis, spermatid development, smell, dendrite/striatum/hippocampus/cerebral cortex/brain development, adult behavior, fat cell differentiation, lipid metabolism regulation, photoreceptor maintenance, retinal rod development, melanosome transport, leptin appetite regulation. These reflect BBS mouse-model phenotypes — pleiotropic ciliopathy downstream effects, not direct molecular functions. KEEP_AS_NON_CORE for the credible ciliopathy-related ones.
• Melanosome transport (ISS): zebrafish bbs4 morphants show melanosome transport delay PMID:24550735; classic BBS assay. Plausible as non-core developmental/transport readout.
• DLEC1 interaction PMID:33144677 — mouse spermatogenesis paper; protein binding IPI.
• Numerous high-throughput interactome IPI protein binding annotations (25416956, 26871637, 27173435, 29039417, 32296183, 32814053, 33961781, 40205054, 18000879=ALDOB, 16327777=CCDC28B). All "protein binding" GO:0005515 — uninformative MF; keep but flag.

Curation strategy summary

• CORE molecular function: protein-macromolecule adaptor activity (GO:0030674) — BBSome cargo adaptor / dynein-PCM1 adaptor. KEEP. Plus the experimentally grounded tubulin/dynactin binding.
• CORE cellular components: BBSome (GO:0034464), centriolar satellite, ciliary membrane, basal body, centrosome, cilium. KEEP experimental ones.
• CORE process: protein localization to cilium / cilium assembly / protein localization to centrosome (PCM1 recruitment), microtubule anchoring at centrosome.
• GO:0005515 protein binding: uninformative per guidelines — mark over-annotated (not core), but do not remove experimental IPIs casually.
• Cell-cycle/cytokinesis terms: secondary RNAi consequences -> MARK_AS_OVER_ANNOTATED.
• nucleus / transcription factor binding: weak; UNDECIDED/non-core.
• ISS pleiotropic developmental terms: KEEP_AS_NON_CORE.