BBS9 (PTHB1; UniProt Q3SYG4) review notes

Identity / overview

Human gene BBS9 (HGNC:30000), aka PTHB1 (Parathyroid hormone-responsive B1 gene). 887 aa, MANE isoform Q3SYG4-1. Chromosome 7. [UniProt Q3SYG4]
Causes autosomal-recessive Bardet–Biedl syndrome type 9 (BBS9; MIM:615986). The recurrent pathogenic missense G141R severely destabilizes the protein [UniProt; PMID:16380913; PMID:26085087].

BBS9 is one of the seven/eight core BBSome subunits (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9, BBIP10/BBIP1). The BBSome is a coat-like adaptor that sorts/traffics specific membrane (signaling-receptor) proteins to and within the primary cilium. PMID:17574030
BBSome assembly is chaperonin-assisted: BBS6/BBS10/BBS12 + CCT/TRiC mediate BBSome assembly; in Mkks(BBS6)-null mice BBS2/BBS7/BBS9 are unstable and degraded, leading to failure of BBSome assembly. [PMID:20080638; PMID:23943788 "in Mkks−/− mice, several BBSome components (e.g. Bbs2, Bbs7 and Bbs9) are unstable and degraded, leading to failure of BBSome assembly"]
Structural basis: BBS9 N-terminal residues 1–407 form a seven-bladed β-propeller (PDB 4YD8, 1.80 Å). BBS9 also has GAE (gamma-adaptin ear), platform/pf, hairpin (hp) and C-terminal α-helical (CtH) domains. With BBS2 and BBS7 it forms the structural core/scaffold of the BBSome (cryo-EM 6XT9, full-length BBS9 modelled). [UniProt REGION 1..407 "Seven-bladed beta-propeller"; PMID:26085087 (structural characterization of BBS9; G141R abolishes stability; Ser142/Tyr186 mutagenesis)]
Residue 141 is "critical for protein stability"; the BBS9 G141R disease variant causes severe loss of protein stability / aberrant folding. [UniProt SITE 141; PMID:26085087]

BBSome / BBS9 localizes both to nonmembranous centriolar satellites in the cytoplasm and to the ciliary membrane. PMID:17574030
ComplexPortal/IDA places the BBSome at the ciliary membrane (GO:0060170). [PMID:19081074, ComplexPortal CPX-1908]
IDA localizations (HPA / GO_Central immunofluorescence and PMID:23943788): cilium (GO:0005929), ciliary transition zone (GO:0035869), ciliary tip (GO:0097542), centriolar satellite (GO:0034451), cytosol (GO:0005829). [GO_REF:0000052; PMID:23943788]
Pericentriolar material (GO:0000242) and cilium IDA from mouse Bbs imaging (MGI). PMID:22139371
UniProt subcellular location: cytoplasm; cytoskeleton/MTOC/centrosome; centriolar satellite; cilium membrane.

BBS9 (and the BBSome) interacts with LZTFL1/BBS17; the BBS9 region 685–765 mediates LZTL1 interaction; LZTFL1 regulates BBSome ciliary trafficking and Smoothened/Hedgehog. [UniProt REGION 685..765; PMID:22072986]
ARL6/BBS3 (small GTPase, not a BBSome subunit) physically interacts with the BBSome; both depend on each other for ciliary localization. BBSome forms normally without Bbs3, but Bbs3 loss mislocalizes ciliary GPCR cargo (MCHR1) and affects retrograde transport. PMID:22139371
AZI1/CEP131 (centriolar satellite protein) interacts with BBS4 and regulates BBSome ciliary trafficking. PMID:24550735
NPHP5(IQCB1)/CEP290 regulate BBSome integrity, ciliary trafficking and cargo delivery. PMID:25552655
Rab8/RAB3IP(Rabin8): BBSome binds Rabin8 (GEF for Rab8), promoting ciliary membrane biogenesis. [PMID:17574030; Reactome R-HSA-5617815]

13 GO:0005515 "protein binding" IPI annotations are uninformative per guidelines; they record specific BBSome subunit / regulator interactions (BBS1, BBS2, BBS4, BBS5, BBS7/TTC8, BBS10, BBS12, LZTFL1, IQCB1, AZI1/CEP131). The informative content is captured by the BBSome part_of (GO:0034464) annotations. Mark protein binding as over-annotated/non-core (keep but not core MF).
The only true MF annotation is ND (GO:0003674). BBS9 has no catalytic activity; it is a structural/scaffolding subunit. A "structural molecule activity" (GO:0005198) MF could be proposed but is not in existing annotations; the BBSome subunit identity (CC) plus protein localization to cilium (BP) capture the function.
fat cell differentiation (GO:0045444) is ISS/IEA from mouse ortholog; plausible BBS-related (obesity) downstream phenotype but indirect / non-core for a structural ciliary subunit -> KEEP_AS_NON_CORE.
cytoplasm (GO:0005737, IEA SubCell) and membrane (GO:0016020) are general/parent terms superseded by more specific IDA terms (centriolar satellite, ciliary membrane). Mark membrane (parent of ciliary membrane) as over-annotated; cytoplasm is acceptable but general.
GO:0061512 protein localization to cilium (IMP, PMID:23943788) and GO:0060271 cilium assembly capture the BP. protein localization to cilium is the more precise/mechanistic core BP (BBSome traffics cargo INTO cilium); cilium assembly is the broader downstream phenotype.

Structural scaffold subunit of the BBSome (β-propeller + GAE/platform/α-helical core, with BBS2/BBS7). [PMID:17574030; PMID:26085087]
BBSome-mediated trafficking of membrane/signaling cargo to and within the primary cilium = protein localization to cilium. [PMID:17574030; PMID:23943788]
Required for ciliogenesis/cilium assembly (downstream). PMID:17574030