BBS2 is a core scaffolding subunit of the BBSome, a stable octameric, coat-like adaptor complex (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP1/BBIP10) that traffics specific membrane proteins, especially signaling receptors such as ciliary G-protein-coupled receptors and Hedgehog-pathway components (e.g. Smoothened), into and out of the primary cilium. BBS2 is a ~721-residue protein built from a coatomer/adaptin-like architecture: an N-terminal beta-propeller, followed by middle, GAE (gamma-adaptin ear), platform and C-terminal helical domains, plus a coiled-coil region; together with BBS7 and BBS9 it forms the beta-propeller/GAE/platform scaffold core of the complex. The BBSome is recruited to the ciliary membrane by the small GTPase ARL6/BBS3-GTP and cooperates with the Rab8 GEF Rabin8 (RAB3IP) and Rab8 to promote ciliary membrane biogenesis and cargo sorting; LZTFL1 regulates its ciliary entry. BBSome-mediated trafficking is required for proper localization and signaling of receptors including the leptin receptor, linking BBS2 to energy homeostasis. BBS2 itself has no catalytic activity; it acts as a structural/adaptor module. The protein localizes to the ciliary membrane, basal body, ciliary transition zone, centriolar satellites and the cytoplasm. Loss-of-function mutations cause autosomal-recessive Bardet-Biedl syndrome (retinal degeneration, obesity, polydactyly, renal anomalies, hypogenitalism, cognitive impairment) and, for certain missense alleles, nonsyndromic retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043005 neuron projection | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) localization to neuron projection. BBS2 acts in the primary cilium, and neuronal primary cilia are a relevant context, but neuron projection is a broad/imprecise CC for a BBSome subunit whose precise site of action is the ciliary membrane/basal body. Reason: BBSome subunits act at the primary cilium; neuron projection is an over-general localization. The specific ciliary localizations (ciliary membrane, basal body, transition zone) are separately and better annotated. |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: BBSome is required for ciliogenesis; phylogenetic inference is consistent with experimental data across species. Reason: Cilium assembly is a core BBSome process well supported across orthologs and by human experimental data. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization. The BBSome is a peripheral coat that associates with the ciliary membrane; the specific term ciliary membrane is already annotated. Reason: Uninformative/over-general CC superseded by GO:0060170 ciliary membrane. |
| GO:0034464 BBSome | IBA GO_REF:0000033 | ACCEPT | Summary: BBSome membership inferred phylogenetically; consistent with abundant experimental evidence. Reason: Core defining feature of BBS2 - it is a structural subunit of the BBSome. |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: Basal-body localization inferred phylogenetically and supported experimentally (IDA PMID:18299575). Reason: Well-supported ciliary localization of BBS2/the BBSome. |
| GO:0031514 motile cilium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Motile-cilium localization inferred phylogenetically; supported by airway motile cilia data (IDA PMID:18299575). Reason: The principal site of action of BBS2 is the primary (non-motile sensory) cilium; motile cilium localization is genuine in ciliated epithelia but is not the core context. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: BBSome assembles and resides in the cytoplasm before/between ciliary entry; consistent with UniProt subcellular location. Reason: Accurate but non-specific background localization; the functionally salient sites are ciliary. |
| GO:0034451 centriolar satellite | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Centriolar-satellite localization is reported (UniProt SubCell; BBS4-dependent recruitment, PMID:24550735), although BBSome function is dispensable for centriolar satellite function. Reason: Genuine localization but non-core; the defining activity of BBS2 is at the ciliary membrane/basal body, not the satellites. |
| GO:0034464 BBSome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic BBSome membership annotation; redundant with experimental annotations. Reason: Correct core localization/complex membership. |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Ciliary membrane localization; supported experimentally (IDA PMID:19081074). Reason: Core localization where the BBSome acts as a membrane coat. |
| GO:1905515 non-motile cilium assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO inference. The primary (non-motile) cilium is precisely the context where the BBSome acts, so this is an appropriately specific process term. Reason: BBSome is required for primary (non-motile/sensory) cilium biogenesis and cargo sorting; this is the most precise process term. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding from a high-throughput interactome (partner PSME3/P61289). Uninformative per curation guidelines. Reason: The protein binding term conveys no specific function; the high-throughput partner is likely non-specific. The relevant molecular role of BBS2 is as a BBSome structural subunit. |
| GO:0005515 protein binding | IPI PMID:17574030 A core complex of BBS proteins cooperates with the GTPase Ra... | MARK AS OVER ANNOTATED | Summary: Protein binding to BBSome subunits (BBS9/Q3SYG4, BBS7/Q8IWZ6, BBS1/Q8NFJ9) identified in BBSome purification. Biologically real but captured by the BBSome membership annotation. Reason: The informative annotation is BBSome complex membership; the protein binding term itself is uninformative. |
| GO:0005515 protein binding | IPI PMID:18000879 Novel interaction partners of Bardet-Biedl syndrome proteins... | MARK AS OVER ANNOTATED | Summary: Protein binding to ALDOB (P05062), tubulin (P68104), KRT8 (Q15154). Generic and likely non-specific. Reason: Uninformative MF term; partners not function-defining for BBS2. |
| GO:0005515 protein binding | IPI PMID:20080638 BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family c... | MARK AS OVER ANNOTATED | Summary: Protein binding to BBSome/assembly partners (BBS9, BBS12, BBS7, MKKS). Real interactions but uninformative MF. Reason: Captured by BBSome membership/assembly biology; the protein binding term is uninformative. |
| GO:0005515 protein binding | IPI PMID:22139371 Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals ... | MARK AS OVER ANNOTATED | Summary: Protein binding to BBS9 (Q3SYG4) from a Bbs3 knockout study. Reason: Uninformative MF term; intra-BBSome interaction already represented by complex membership. |
| GO:0005515 protein binding | IPI PMID:22500027 Intrinsic protein-protein interaction-mediated and chaperoni... | MARK AS OVER ANNOTATED | Summary: Protein binding to BBSome subunits (BBS9, BBS7, BBS1, MKKS) in the BBSome assembly study. Reason: Uninformative MF term; intra-complex interactions captured by BBSome membership. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic protein-binding from a high-throughput interactome (PSME3, RBPMS, MDFI). Reason: Uninformative; high-throughput partners likely non-specific. |
| GO:0005515 protein binding | IPI PMID:25552655 Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integ... | MARK AS OVER ANNOTATED | Summary: Protein binding to IQCB1/NPHP5 (Q15051), which regulates BBSome integrity and ciliary cargo delivery. Biologically meaningful interaction but uninformative as an MF term. Reason: The protein binding term is uninformative; the regulatory relationship is better captured at the process level. |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | MARK AS OVER ANNOTATED | Summary: Protein binding to BBSome subunits from organellar proteomics. Reason: Uninformative MF term. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding (BBS7) from a high-throughput AP-MS interactome. Reason: Uninformative MF term. |
| GO:0005515 protein binding | IPI PMID:29039417 Protein interaction perturbation profiling at amino-acid res... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding (BBS7) from interaction perturbation profiling. Reason: Uninformative MF term. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein-binding from the HuRI binary interactome (HNRNPF, PSME3, LMO4, NRF1, RBPMS, FNDC3B). Several partners are likely non-specific. Reason: Uninformative MF term; high-throughput Y2H partners not function-defining. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding (BBS1, BBS7) from a high-throughput interactome. Reason: Uninformative MF term; intra-BBSome interactions captured by membership. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding (BBS7, BBS1) from multimodal cell mapping. Reason: Uninformative MF term. |
| GO:0005902 microvillus | IEA GO_REF:0000107 | REMOVE | Summary: Electronic Ensembl-Compara transfer from mouse. There is no robust evidence that BBS2 localizes to or acts at microvilli; BBSome subunits act at cilia, not microvilli. Reason: Over-propagated electronic annotation lacking biological support; likely conflation with ciliary/apical structures. Not supported by primary data. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization (electronic transfer). Reason: Over-general; superseded by ciliary membrane (GO:0060170). |
| GO:0031514 motile cilium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Motile-cilium localization (electronic transfer); supported by airway motile-cilia data. Reason: Genuine in ciliated epithelia but not the core (primary cilium) context. |
| GO:0032420 stereocilium | IEA GO_REF:0000107 | REMOVE | Summary: Electronic Ensembl transfer from mouse. Evidence for genuine BBS2 localization to stereocilia (actin-based, non-ciliary structures) is weak. Reason: Over-propagated electronic annotation; stereocilia are actin-based hair bundles distinct from cilia, and there is no robust support for BBS2 acting there. |
| GO:0038108 negative regulation of appetite by leptin-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse. Supported by the leptin-resistance phenotype of Bbs2-/- mice and a role for BBS proteins in leptin receptor trafficking/signaling. Reason: Biologically supported organismal/physiological process downstream of BBSome-mediated receptor trafficking, not a direct molecular function of BBS2. |
| GO:0045444 fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse; BBS proteins are implicated in adipogenesis/obesity. Reason: Plausible but indirect organismal phenotype; not a direct BBS2 molecular function. |
| GO:0060271 cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of the core ciliogenesis role. Reason: Core BBSome process, also supported experimentally. |
| GO:0060296 regulation of cilium beat frequency involved in ciliary motility | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from mouse. Bbs loss alters motile-cilia morphology and function in airway epithelia (PMID:18299575), but a direct role for BBS2 in regulating ciliary beat frequency is weak; the core role of the BBSome is in sensory (non-motile) cilia. Reason: Indirect/over-propagated; motility defects are likely secondary to ciliary trafficking/biogenesis defects rather than direct beat-frequency regulation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617815 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (BBSome binds RAB3IP/Rabin8). Consistent with the cytoplasmic pool of the BBSome. Reason: Accurate background localization; the functionally salient sites are ciliary. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624125 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (Formation of the BBSome). Reason: BBSome assembly occurs in the cytoplasm; accurate but non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624126 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (ARL6:GTP and the BBSome bind ciliary cargo). Reason: Accurate but non-core background localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624127 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (ARL6:GTP and the BBSome target cargo to the cilium). Reason: Accurate but non-core background localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5624129 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (LZTFL1 binds the BBSome). Reason: Accurate but non-core background localization. |
| GO:0035869 ciliary transition zone | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localization to the ciliary transition zone, a gate region at the ciliary base where the BBSome operates. Reason: Experimentally supported ciliary localization consistent with BBSome cargo gating. |
| GO:0034464 BBSome | IPI PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... | ACCEPT | Summary: ComplexPortal IPI evidence for BBSome membership. Reason: Core defining feature of BBS2. Supporting Evidence: PMID:19081074 BBS proteins form a stable complex, the BBSome |
| GO:0060170 ciliary membrane | IDA PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... | ACCEPT | Summary: Direct-assay ciliary membrane localization. Reason: Core localization of the BBSome coat. |
| GO:0060271 cilium assembly | NAS PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, ... | ACCEPT | Summary: BBSome subunit role in ciliogenesis (non-traceable author statement), consistent with experimental evidence. Reason: Core BBSome process. Supporting Evidence: PMID:19081074 A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. |
| GO:0034464 BBSome | IMP PMID:19150989 Requirement of Bardet-Biedl syndrome proteins for leptin rec... | ACCEPT | Summary: MGI IMP-supported BBSome membership; the leptin study uses Bbs2-/- mice and frames BBS2 as a BBSome subunit. Reason: Core defining feature of BBS2. Supporting Evidence: PMID:19150989 form a stable complex known as the BBSome |
| GO:0005515 protein binding | IPI PMID:33144677 Dlec1 is required for spermatogenesis and male fertility in ... | MARK AS OVER ANNOTATED | Summary: Protein binding to DLEC1 (Q9Y238) from a spermatogenesis study. Real interaction but uninformative MF term. Reason: The protein binding term is uninformative; partner not function-defining for BBS2. |
| GO:0005515 protein binding | IPI PMID:18762586 Recruitment of PCM1 to the centrosome by the cooperative act... | MARK AS OVER ANNOTATED | Summary: Protein binding to PCM1 (Q9NRI5) from a PCM1/DISC1/BBS4-centric centrosomal-recruitment study. Real interaction but uninformative MF term. Reason: The protein binding term is uninformative; the PCM1 interaction is centrosome/satellite-related and not function-defining for BBS2. |
| GO:0007601 visual perception | IMP PMID:25541840 Association between missense mutations in the BBS2 gene and ... | KEEP AS NON CORE | Summary: BBS2 missense mutations cause nonsyndromic retinitis pigmentosa (RP74), implicating BBS2 in vision via photoreceptor (connecting cilium) function. Reason: Genuine, experimentally/genetically supported organismal role, but a downstream physiological consequence of the ciliary-trafficking function of BBS2 rather than a direct molecular activity. |
| GO:0034464 BBSome | IDA PMID:24550735 The centriolar satellite protein AZI1 interacts with BBS4 an... | ACCEPT | Summary: Direct-assay BBSome membership. Reason: Core defining feature of BBS2. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:22302990 Direct role of Bardet-Biedl syndrome proteins in transcripti... | MARK AS OVER ANNOTATED | Summary: Annotation derives from a BBS7-centric study reporting interaction with the PcG protein RNF2 (Q99496) and proposing a transcriptional role for BBS proteins generally. For BBS2 specifically this is indirect, and a nuclear transcriptional function is contested against the well-established cytoplasmic/ciliary trafficking role. Reason: Weak, indirect support for BBS2; the proposed transcriptional role is disputed and not a core function. Retained (not removed) as it derives from an experimental interaction annotation, but flagged as over-annotation. |
| GO:0005515 protein binding | IPI PMID:16327777 Dissection of epistasis in oligogenic Bardet-Biedl syndrome. | MARK AS OVER ANNOTATED | Summary: Protein binding to CCDC28B (Q9BUN5), a BBS modifier. Real interaction but uninformative MF term. Reason: The protein binding term is uninformative; better captured at the complex/process level. |
| GO:0038108 negative regulation of appetite by leptin-mediated signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse; supported by Bbs2-/- leptin resistance and BBS-mediated leptin receptor trafficking. Reason: Supported physiological role downstream of receptor trafficking; not a direct molecular function. |
| GO:0043001 Golgi to plasma membrane protein transport | IMP PMID:19150989 Requirement of Bardet-Biedl syndrome proteins for leptin rec... | KEEP AS NON CORE | Summary: BBS2 depletion mistraffics the leptin receptor between the Golgi and the plasma/ciliary membrane (large perinuclear vesicles), supporting a role in Golgi-to-surface receptor transport. Reason: Experimentally supported trafficking role, but secondary to / a facet of the core ciliary membrane-protein trafficking activity of the BBSome. Supporting Evidence: PMID:19150989 similar mistrafficking of LepRb when BBS2 protein was depleted |
| GO:0032402 melanosome transport | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity transfer (with reference UniProtKB:Q98SP7, a non-mammalian ortholog). Evidence for a genuine melanosome-transport role of human BBS2 is weak. Reason: Over-propagated ISS from a distant ortholog; not supported by mammalian experimental data and inconsistent with the ciliary-trafficking function of BBS2. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the core ciliogenesis role. Reason: Core BBSome process, supported by direct evidence. |
| GO:0060296 regulation of cilium beat frequency involved in ciliary motility | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity transfer from mouse; same caveats as the IEA version - the core role of BBS2 is in sensory cilia, and motility effects are likely indirect. Reason: Indirect; beat-frequency effects are downstream of trafficking/biogenesis defects rather than a direct BBS2 function. |
| GO:0007288 sperm axoneme assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse. BBS proteins/BBSome contribute to flagellar/ciliary trafficking, and BBS2 interacts with DLEC1 (a spermatogenesis factor), giving plausible but indirect support. Reason: Plausible flagellar (cilium-related) role but indirect and tissue- specific; not a core function. |
| GO:0008104 intracellular protein localization | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Broad process term capturing the BBSome's role in localizing membrane-protein cargo. Accurate in essence but too general. Reason: Over-general; the specific trafficking processes (ciliary membrane-protein sorting/cilium assembly) are the informative annotations. |
| GO:0021756 striatum development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse brain-development phenotypes of Bbs2 loss. Reason: Downstream organismal/developmental consequence of ciliary dysfunction, not a direct BBS2 molecular function. |
| GO:0021766 hippocampus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse brain-development phenotypes. Reason: Downstream developmental consequence of ciliary dysfunction. |
| GO:0021987 cerebral cortex development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse brain-development phenotypes. Reason: Downstream developmental consequence of ciliary dysfunction. |
| GO:0030534 adult behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse behavioral phenotypes of Bbs2 loss. Reason: Downstream organismal phenotype, not a direct molecular function. |
| GO:0040015 negative regulation of multicellular organism growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse growth phenotypes. Reason: Downstream organismal phenotype; not a direct molecular function. |
| GO:0045444 fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (duplicate of the IEA version); BBS/adipogenesis link. Reason: Plausible but indirect organismal phenotype. |
| GO:0045494 photoreceptor cell maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer; consistent with retinal degeneration in BBS2 and nonsyndromic RP74 (PMID:25541840), reflecting the role of the connecting cilium / BBSome trafficking in photoreceptors. Reason: Genuine tissue-specific role downstream of ciliary trafficking; not a direct molecular function. |
| GO:0048854 brain morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from mouse neurodevelopmental phenotypes. Reason: Downstream developmental consequence of ciliary dysfunction. |
| GO:0034464 BBSome | IDA PMID:17574030 A core complex of BBS proteins cooperates with the GTPase Ra... | ACCEPT | Summary: Direct-assay BBSome membership from the founding BBSome purification. Reason: Core defining feature of BBS2. Supporting Evidence: PMID:17574030 A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. |
| GO:0031514 motile cilium | IDA PMID:18299575 Loss of Bardet-Biedl syndrome proteins alters the morphology... | KEEP AS NON CORE | Summary: Direct localization to motile cilia of airway epithelia. Reason: Genuine localization in ciliated epithelia but not the core (primary cilium) context. Supporting Evidence: PMID:18299575 BBS2 and BBS4 localized to cellular structures associated with motile cilia |
| GO:0036064 ciliary basal body | IDA PMID:18299575 Loss of Bardet-Biedl syndrome proteins alters the morphology... | ACCEPT | Summary: Direct localization to the ciliary basal body. Reason: Core ciliary localization of BBS2/the BBSome. Supporting Evidence: PMID:18299575 BBS2 and BBS4 localized to cellular structures associated with motile cilia |
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Download this section (compressed HTML)Q: Does BBS2 have any cargo-recognition role distinct from its scaffolding function, or is cargo selectivity entirely conferred by other subunits (e.g. BBS1, BBS5, BBS9)?
Q: Is the reported nuclear/transcriptional role of BBS proteins (RNF2 interaction) biologically significant for BBS2 specifically, or restricted to BBS7?
Q: To what extent are the brain-development, behavior and growth phenotypes of Bbs2 loss direct, versus secondary to systemic ciliary signaling defects?
Experiment: Cryo-EM of the human BBSome with and without BBS2 to define BBS2's structural contacts and the consequences of pathogenic missense variants (e.g. D104A, R632P) on complex integrity.
Hypothesis: BBS2 missense variants destabilize specific scaffold contacts within the BBSome.
Experiment: Quantitative ciliary proteomics (e.g. cilium-APEX) in BBS2-null versus wild-type cells to define the full set of receptor cargoes whose ciliary localization depends on BBS2.
Hypothesis: BBS2 loss selectively depletes a defined set of GPCR/receptor cargoes from the ciliary membrane.
Experiment: Structure-function analysis of BBS2 missense alleles causing syndromic BBS versus nonsyndromic RP74 to determine whether RP-specific alleles selectively impair photoreceptor-relevant cargo trafficking.
Hypothesis: RP74-specific BBS2 alleles retain general BBSome function but impair trafficking of photoreceptor-specific cargo.
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