{"gene":"FAM91A1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structure of the human WDR11-FAM91A1 complex was determined, revealing that WDR11 directly and specifically recognizes a subset of acidic clusters termed 'super acidic clusters' (SACs) on cargo proteins. The complex functions downstream of the clathrin-associated AP-1 complex to facilitate protein transport from endosomes to the TGN, and its assembly and SAC-binding are indispensable for proper trafficking of SAC-containing proteins.","method":"Cryo-EM structure determination, biochemical binding assays, zebrafish developmental assays (loss-of-function)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation in vivo, multiple orthogonal methods in a single rigorous study","pmids":["39013469"],"is_preprint":false},{"year":2023,"finding":"FAM91A1 directly interacts with TBC1D23, an established pontocerebellar hypoplasia (PCH) gene product, and cooperates with it to regulate endosome-to-Golgi trafficking of KIAA0319L (a regulator of axonal growth). Crystal structure of the FAM91A1-TBC1D23 complex shows TBC1D23 binds a conserved surface on FAM91A1 in a Z-shaped conformation. Depletion of FAM91A1 in zebrafish causes developmental defects similar to TBC1D23 depletion.","method":"Crystal structure determination, direct protein interaction assays, zebrafish knockdown/loss-of-function with developmental phenotype readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vivo epistasis (zebrafish) plus direct interaction assays, multiple orthogonal methods in a single rigorous study","pmids":["37903274"],"is_preprint":false},{"year":2014,"finding":"FAM91A1 was identified as a component of the dysbindin-associated proteome in the P2 synaptosome fraction of mouse brain, and its interaction with dysbindin (DTNBP1) was verified by co-immunoprecipitation. FAM91A1 also co-purified with WDR11 in the same complex.","method":"Immunopurification from BAC transgenic mouse brain P2 fraction, mass spectrometry, co-immunoprecipitation verification","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP verification in brain synaptosome fraction, single lab but two orthogonal methods (MS + co-IP)","pmids":["25198678"],"is_preprint":false}],"current_model":"FAM91A1 forms a stable complex with WDR11 that acts downstream of the AP-1 clathrin coat to facilitate endosome-to-TGN trafficking by directly recognizing super acidic cluster (SAC) sequences on cargo proteins; it also directly interacts with TBC1D23 (a PCH gene product) to cooperate in endosomal trafficking of the axonal regulator KIAA0319L, and loss of FAM91A1 in zebrafish causes neurodevelopmental defects consistent with disrupted endosomal trafficking underlying pontocerebellar hypoplasia."},"narrative":{"mechanistic_narrative":"FAM91A1 is a subunit of an endosome-to-trans-Golgi-network (TGN) trafficking module that operates downstream of the clathrin-associated AP-1 coat [PMID:39013469]. It forms a stable complex with WDR11, in which WDR11 directly and specifically recognizes 'super acidic cluster' (SAC) sequences on cargo proteins; assembly of the WDR11-FAM91A1 complex and its SAC-binding activity are both required for correct trafficking of SAC-containing cargo from endosomes to the TGN [PMID:39013469]. FAM91A1 also directly binds the pontocerebellar hypoplasia (PCH) gene product TBC1D23 through a conserved surface, adopting a Z-shaped interface, and cooperates with TBC1D23 to direct endosome-to-Golgi trafficking of the axonal-growth regulator KIAA0319L [PMID:37903274]. Loss of FAM91A1 in zebrafish produces developmental defects mirroring those of TBC1D23 depletion, linking this trafficking activity to the neurodevelopmental pathology of PCH [PMID:37903274]. The complex was originally detected in brain synaptosomes as part of the dysbindin (DTNBP1)-associated proteome, co-purifying with WDR11 [PMID:25198678].","teleology":[{"year":2014,"claim":"Established FAM91A1 as a physical component of a brain protein assembly, placing it within the dysbindin-associated proteome and linking it to WDR11 before any function was known.","evidence":"Immunopurification from BAC transgenic mouse brain P2 synaptosome fraction with mass spectrometry and co-IP verification","pmids":["25198678"],"confidence":"Medium","gaps":["Functional role of the FAM91A1-WDR11 association not addressed","Significance of the dysbindin interaction in trafficking left unresolved","No structural or mechanistic detail of the complex"]},{"year":2023,"claim":"Resolved how FAM91A1 contributes to neurodevelopment by showing it directly binds the PCH gene product TBC1D23 and cooperates in trafficking the axonal regulator KIAA0319L.","evidence":"Crystal structure of the FAM91A1-TBC1D23 complex, direct interaction assays, and zebrafish loss-of-function with developmental phenotype readout","pmids":["37903274"],"confidence":"High","gaps":["Does not define how cargo specificity is achieved at the molecular level","Relationship between the TBC1D23 interaction and the WDR11 complex not integrated"]},{"year":2024,"claim":"Defined the molecular mechanism of the WDR11-FAM91A1 complex as a cargo-recognition module acting downstream of AP-1, with WDR11 reading 'super acidic cluster' motifs to route cargo from endosomes to the TGN.","evidence":"Cryo-EM structure of the human WDR11-FAM91A1 complex, biochemical binding assays, and zebrafish loss-of-function assays","pmids":["39013469"],"confidence":"High","gaps":["Catalytic or enzymatic role (if any) of FAM91A1 within the complex not established","Full cargo repertoire bearing SAC motifs not enumerated","How the AP-1 coat hands cargo to the WDR11-FAM91A1 complex mechanistically undefined"]},{"year":null,"claim":"How the WDR11-FAM91A1-TBC1D23 trafficking activities are coordinated into a single pathway, and the complete set of SAC-bearing cargoes whose mistrafficking drives pontocerebellar hypoplasia, remain to be defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking SAC recognition and TBC1D23-dependent KIAA0319L trafficking","Causative human FAM91A1 mutations not reported in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]}],"complexes":["WDR11-FAM91A1 complex"],"partners":["WDR11","TBC1D23","DTNBP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q658Y4","full_name":"Protein FAM91A1","aliases":[],"length_aa":838,"mass_kda":93.9,"function":"As component of the WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1","subcellular_location":"Golgi apparatus, trans-Golgi network; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q658Y4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM91A1","classification":"Not Classified","n_dependent_lines":74,"n_total_lines":1208,"dependency_fraction":0.061258278145695365},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DRG1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FAM91A1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM91A1"},"hgnc":{"alias_symbol":["FLJ23790"],"prev_symbol":[]},"alphafold":{"accession":"Q658Y4","domains":[{"cath_id":"-","chopping":"240-281_375-523","consensus_level":"medium","plddt":81.659,"start":240,"end":523},{"cath_id":"-","chopping":"531-667_717-777","consensus_level":"high","plddt":89.3471,"start":531,"end":777},{"cath_id":"1.10.10","chopping":"2-59","consensus_level":"medium","plddt":88.7191,"start":2,"end":59}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q658Y4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q658Y4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q658Y4-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM91A1","jax_strain_url":"https://www.jax.org/strain/search?query=FAM91A1"},"sequence":{"accession":"Q658Y4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q658Y4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q658Y4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q658Y4"}},"corpus_meta":[{"pmid":"33413557","id":"PMC_33413557","title":"NRG1 fusions in breast cancer.","date":"2021","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/33413557","citation_count":23,"is_preprint":false},{"pmid":"39013469","id":"PMC_39013469","title":"The WDR11 complex is a receptor for acidic-cluster-containing cargo proteins.","date":"2024","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/39013469","citation_count":16,"is_preprint":false},{"pmid":"25198678","id":"PMC_25198678","title":"Dysbindin-associated proteome in the p2 synaptosome fraction of mouse brain.","date":"2014","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/25198678","citation_count":12,"is_preprint":false},{"pmid":"37903274","id":"PMC_37903274","title":"FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37903274","citation_count":11,"is_preprint":false},{"pmid":"35610231","id":"PMC_35610231","title":"The regulatory mechanism of LncRNA-mediated ceRNA network in osteosarcoma.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35610231","citation_count":10,"is_preprint":false},{"pmid":"27520307","id":"PMC_27520307","title":"AK048794 maintains the mouse embryonic stem cell pluripotency by functioning as an miRNA sponge for miR-592.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27520307","citation_count":10,"is_preprint":false},{"pmid":"26918048","id":"PMC_26918048","title":"Proton Beams Inhibit Proliferation of Breast Cancer Cells by Altering DNA Methylation Status.","date":"2016","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26918048","citation_count":7,"is_preprint":false},{"pmid":"35456988","id":"PMC_35456988","title":"Squalene through Its Post-Squalene Metabolites Is a Modulator of Hepatic Transcriptome in Rabbits.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35456988","citation_count":4,"is_preprint":false},{"pmid":"36606427","id":"PMC_36606427","title":"Integrative analysis of the proteome and transcriptome in gastric cancer identified LRP1B as a potential biomarker.","date":"2023","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36606427","citation_count":4,"is_preprint":false},{"pmid":"34761370","id":"PMC_34761370","title":"Fetal Neuroprotective Mechanism of Maternal Magnesium Sulfate: Proteomic Analysis.","date":"2021","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/34761370","citation_count":2,"is_preprint":false},{"pmid":"40162875","id":"PMC_40162875","title":"LTD1 plays a key role in rice tillering regulation through cooperation with CycH1;1 and TFB2 subunits of the TFIIH complex.","date":"2025","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40162875","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7588,"output_tokens":932,"usd":0.018372,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7413,"output_tokens":1768,"usd":0.040633,"stage2_stop_reason":"end_turn"},"total_usd":0.059005,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the human WDR11-FAM91A1 complex was determined, revealing that WDR11 directly and specifically recognizes a subset of acidic clusters termed 'super acidic clusters' (SACs) on cargo proteins. The complex functions downstream of the clathrin-associated AP-1 complex to facilitate protein transport from endosomes to the TGN, and its assembly and SAC-binding are indispensable for proper trafficking of SAC-containing proteins.\",\n      \"method\": \"Cryo-EM structure determination, biochemical binding assays, zebrafish developmental assays (loss-of-function)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation in vivo, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"39013469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM91A1 directly interacts with TBC1D23, an established pontocerebellar hypoplasia (PCH) gene product, and cooperates with it to regulate endosome-to-Golgi trafficking of KIAA0319L (a regulator of axonal growth). Crystal structure of the FAM91A1-TBC1D23 complex shows TBC1D23 binds a conserved surface on FAM91A1 in a Z-shaped conformation. Depletion of FAM91A1 in zebrafish causes developmental defects similar to TBC1D23 depletion.\",\n      \"method\": \"Crystal structure determination, direct protein interaction assays, zebrafish knockdown/loss-of-function with developmental phenotype readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vivo epistasis (zebrafish) plus direct interaction assays, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"37903274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FAM91A1 was identified as a component of the dysbindin-associated proteome in the P2 synaptosome fraction of mouse brain, and its interaction with dysbindin (DTNBP1) was verified by co-immunoprecipitation. FAM91A1 also co-purified with WDR11 in the same complex.\",\n      \"method\": \"Immunopurification from BAC transgenic mouse brain P2 fraction, mass spectrometry, co-immunoprecipitation verification\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP verification in brain synaptosome fraction, single lab but two orthogonal methods (MS + co-IP)\",\n      \"pmids\": [\"25198678\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM91A1 forms a stable complex with WDR11 that acts downstream of the AP-1 clathrin coat to facilitate endosome-to-TGN trafficking by directly recognizing super acidic cluster (SAC) sequences on cargo proteins; it also directly interacts with TBC1D23 (a PCH gene product) to cooperate in endosomal trafficking of the axonal regulator KIAA0319L, and loss of FAM91A1 in zebrafish causes neurodevelopmental defects consistent with disrupted endosomal trafficking underlying pontocerebellar hypoplasia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM91A1 is a subunit of an endosome-to-trans-Golgi-network (TGN) trafficking module that operates downstream of the clathrin-associated AP-1 coat [#0]. It forms a stable complex with WDR11, in which WDR11 directly and specifically recognizes 'super acidic cluster' (SAC) sequences on cargo proteins; assembly of the WDR11-FAM91A1 complex and its SAC-binding activity are both required for correct trafficking of SAC-containing cargo from endosomes to the TGN [#0]. FAM91A1 also directly binds the pontocerebellar hypoplasia (PCH) gene product TBC1D23 through a conserved surface, adopting a Z-shaped interface, and cooperates with TBC1D23 to direct endosome-to-Golgi trafficking of the axonal-growth regulator KIAA0319L [#1]. Loss of FAM91A1 in zebrafish produces developmental defects mirroring those of TBC1D23 depletion, linking this trafficking activity to the neurodevelopmental pathology of PCH [#1]. The complex was originally detected in brain synaptosomes as part of the dysbindin (DTNBP1)-associated proteome, co-purifying with WDR11 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established FAM91A1 as a physical component of a brain protein assembly, placing it within the dysbindin-associated proteome and linking it to WDR11 before any function was known.\",\n      \"evidence\": \"Immunopurification from BAC transgenic mouse brain P2 synaptosome fraction with mass spectrometry and co-IP verification\",\n      \"pmids\": [\"25198678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of the FAM91A1-WDR11 association not addressed\",\n        \"Significance of the dysbindin interaction in trafficking left unresolved\",\n        \"No structural or mechanistic detail of the complex\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how FAM91A1 contributes to neurodevelopment by showing it directly binds the PCH gene product TBC1D23 and cooperates in trafficking the axonal regulator KIAA0319L.\",\n      \"evidence\": \"Crystal structure of the FAM91A1-TBC1D23 complex, direct interaction assays, and zebrafish loss-of-function with developmental phenotype readout\",\n      \"pmids\": [\"37903274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define how cargo specificity is achieved at the molecular level\",\n        \"Relationship between the TBC1D23 interaction and the WDR11 complex not integrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the molecular mechanism of the WDR11-FAM91A1 complex as a cargo-recognition module acting downstream of AP-1, with WDR11 reading 'super acidic cluster' motifs to route cargo from endosomes to the TGN.\",\n      \"evidence\": \"Cryo-EM structure of the human WDR11-FAM91A1 complex, biochemical binding assays, and zebrafish loss-of-function assays\",\n      \"pmids\": [\"39013469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Catalytic or enzymatic role (if any) of FAM91A1 within the complex not established\",\n        \"Full cargo repertoire bearing SAC motifs not enumerated\",\n        \"How the AP-1 coat hands cargo to the WDR11-FAM91A1 complex mechanistically undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the WDR11-FAM91A1-TBC1D23 trafficking activities are coordinated into a single pathway, and the complete set of SAC-bearing cargoes whose mistrafficking drives pontocerebellar hypoplasia, remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No unified model linking SAC recognition and TBC1D23-dependent KIAA0319L trafficking\",\n        \"Causative human FAM91A1 mutations not reported in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"WDR11-FAM91A1 complex\"],\n    \"partners\": [\"WDR11\", \"TBC1D23\", \"DTNBP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}