#!/usr/bin/env python3 """Build modules/primary_cilium_life_cycle.yaml from a compact curated spec. The spec below is the curated content (stages, roles, GO terms, citations). UniProt accessions and names are NOT typed here: they are read from cilium_life_cycle/candidate_members.yaml, which was populated from the UniProt REST API. GO ids in the spec were checked against OLS (2026-10-03); PMIDs were checked against PubMed. Usage (from repo root): uv run python projects/HUMAN_PROTEIN_ATLAS/scripts/build_cilium_module.py """ import re from pathlib import Path import yaml WORK = Path("projects/HUMAN_PROTEIN_ATLAS/cilium_life_cycle") OUT = Path("modules/primary_cilium_life_cycle.yaml") MEMBERS = {r["gene"]: r for r in yaml.safe_load((WORK / "candidate_members.yaml").read_text())["members"]} GO = { "GO:0044782": "cilium organization", "GO:0060271": "cilium assembly", "GO:1905515": "non-motile cilium assembly", "GO:0061523": "cilium disassembly", "GO:1905349": "ciliary transition zone assembly", "GO:1905556": "ciliary vesicle assembly", "GO:0042073": "intraciliary transport", "GO:0035720": "intraciliary anterograde transport", "GO:0035721": "intraciliary retrograde transport", "GO:0061512": "protein localization to cilium", "GO:1902017": "regulation of cilium assembly", "GO:1902018": "negative regulation of cilium assembly", "GO:0007019": "microtubule depolymerization", "GO:0003924": "GTPase activity", "GO:0004674": "protein serine/threonine kinase activity", "GO:0004439": "phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity", "GO:0005085": "guanyl-nucleotide exchange factor activity", "GO:0005096": "GTPase activator activity", "GO:0008574": "plus-end-directed microtubule motor activity", "GO:0008569": "minus-end-directed microtubule motor activity", "GO:0042903": "tubulin deacetylase activity", "GO:0030992": "intraciliary transport particle B", "GO:0030991": "intraciliary transport particle A", "GO:0016939": "kinesin II complex", "GO:0036038": "MKS complex", "GO:0035869": "ciliary transition zone", "GO:0036064": "ciliary basal body", "GO:0097721": "ciliary vesicle", "GO:0060170": "ciliary membrane", "GO:0005930": "axoneme", "GO:0097542": "ciliary tip", "GO:0097730": "non-motile cilium", "GO:0034451": "centriolar satellite", "GO:0003925": "G protein activity", "GO:0001918": "farnesylated protein binding", "GO:0043539": "protein serine/threonine kinase activator activity", "GO:0030295": "protein kinase activator activity", "GO:0008289": "lipid binding", "GO:1903441": "protein localization to ciliary membrane", "GO:0030674": "protein-macromolecule adaptor activity", "GO:0015631": "tubulin binding", "GO:0140597": "protein carrier activity", "GO:0051010": "microtubule plus-end binding", "GO:0005814": "centriole", "GO:0030050": "vesicle transport along actin filament", "GO:0000146": "microfilament motor activity", "GO:0016887": "ATP hydrolysis activity", "GO:0031115": "negative regulation of microtubule polymerization", "GO:1902856": "negative regulation of non-motile cilium assembly", "GO:0005868": "cytoplasmic dynein complex", } HPA_ATLAS = { "source_id": "PMID:41005307", "title": "Intrinsic heterogeneity of primary cilia revealed through spatial proteomics.", } def term(go_id): return {"id": go_id, "label": GO[go_id]} def concept(go_id, description=None): d = {"preferred_term": GO[go_id], "term": term(go_id)} if description: d["description"] = description return d def protein(gene): m = MEMBERS[gene] name = re.split(r" \(|\s\[", m["protein_name"])[0] return {"preferred_term": gene, "term": {"id": f"UniProtKB:{m['uniprot']}", "label": name}} def gp(gene): return {"selector_type": "GENE_PRODUCT", "gene_product": protein(gene)} def ev(pmid, statement, title=None): d = {"source_id": pmid} if title: d["title"] = title d["statement"] = statement return d def annoton(aid, label, participant, role, fn=None, fn_label=None, fn_desc=None, processes=(), locations=(), evidence=()): a = {"id": aid, "label": label, "participant": participant} if fn: a["function"] = {"preferred_term": fn_label or GO[fn], "term": term(fn)} elif fn_label: a["function"] = {"preferred_term": fn_label} if fn_desc: a["function"]["description"] = fn_desc if processes: a["processes"] = [concept(p) for p in processes] if locations: a["locations"] = [concept(loc) for loc in locations] a["role_description"] = role if evidence: a["evidence"] = list(evidence) return a def complex_sel(name, desc, genes, role, go_id=None): pc = {"preferred_term": name} if go_id: pc["term"] = term(go_id) return { "selector_type": "PROTEIN_COMPLEX", "protein_complex": { **pc, "description": desc, "active_units": [ {"id": f"{g.lower()}_unit", "label": f"{g} subunit", "participant": gp(g), "role": role} for g in genes ], }, } def kinesin2_sel(): """Heterotrimeric kinesin II: KIF3A/KIF3B motors plus the KIFAP3 cargo adaptor.""" sel = complex_sel("kinesin-2 (KIF3A/KIF3B/KIFAP3)", "Heterotrimeric kinesin II motor.", ["KIF3A", "KIF3B"], "kinesin-2 motor subunit", "GO:0016939") sel["protein_complex"]["active_units"].append({ "id": "kifap3_unit", "label": "KIFAP3 subunit", "participant": gp("KIFAP3"), "role": "non-motor cargo adaptor subunit", "function": {"preferred_term": GO["GO:0030674"], "term": term("GO:0030674")}, }) return sel # ---------------------------------------------------------------- stages TANOS = ev("PMID:23348840", "Identifies CEP83, CEP89, SCLT1, FBF1 and CEP164 as distal appendage components, " "defines their assembly hierarchy, and shows that undocked centrioles fail to recruit TTBK2 or release CP110.", "Centriole distal appendages promote membrane docking, leading to cilia initiation.") GOETZ = ev("PMID:23141541", "TTBK2 acts at the distal end of the basal body, promotes removal of the CP110 cap and " "recruitment of IFT proteins, and is required to initiate ciliogenesis.", "The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.") KOBAYASHI = ev("PMID:21620453", "KIF24 binds CP110 and CEP97 at the mother centriole, depolymerizes microtubules in vitro, " "and restrains cilia assembly in cycling cells.", "Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis.") LU = ev("PMID:25686250", "EHD1 and EHD3 tubulate membranes to fuse distal appendage vesicles into the ciliary vesicle, " "acting with the Rab11-Rab8 cascade; Rab8 is activated only after ciliary vesicle assembly.", "Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation.") WU = ev("PMID:29335527", "Myosin-Va transports preciliary vesicles to the mother centriole, the earliest known step of " "ciliary vesicle formation.", "Myosin-Va is required for preciliary vesicle transportation to the mother centriole during ciliogenesis.") NACHURY = ev("PMID:17574030", "Rab8-GTP, produced by the Rab8 GEF Rabin8 at the basal body, enters the cilium and " "promotes ciliary membrane extension.", "A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.") GARCIA = ev("PMID:21725307", "TCTN1 forms a transition zone complex with MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN2 and " "CC2D2A that controls ciliogenesis and ciliary membrane composition in a tissue-specific manner.", "A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.") PAZOUR = ev("PMID:11062270", "IFT88 and its mouse homologue Tg737 are required for cilium and flagellum assembly.", "Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for " "assembly of cilia and flagella.") TASCHNER = ev("PMID:36354106", "Biochemically validated structural model of the 15-subunit IFT-B complex.", "Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B.") IFTA = ev("PMID:36775821", "Structures of the human IFT-A complex provide the molecular basis of IFT-A in ciliary transport.", "Human IFT-A complex structures provide molecular insights into ciliary transport.") TOROPOVA = ev("PMID:31451806", "Structure of the dynein-2 complex and its assembly onto IFT trains for retrograde transport.", "Structure of the dynein-2 complex and its assembly with intraflagellar transport trains.") GOTTHARDT = ev("PMID:26551564", "ARL13B is the guanine nucleotide exchange factor for ARL3, creating a G-protein cascade " "that releases lipidated cargo from PDE6D and UNC119 inside the cilium.", "A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins.") TULP3 = ev("PMID:20889716", "TULP3 bridges the IFT-A complex and membrane phosphoinositides to traffic G protein-coupled " "receptors into cilia.", "TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled " "receptors into primary cilia.") INPP5E_EV = ev("PMID:19668215", "INPP5E localizes to cilia; its loss causes ciliary signaling defects and ciliary instability.", "INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human " "and mouse.") ICK = ev("PMID:24853502", "Intestinal cell kinase (CILK1) is a key regulator of cilia length and signaling.", "Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key " "regulator of cilia length and Hedgehog signaling.") ICK_MOK = ev("PMID:25243405", "The RCK kinases ICK and MOK regulate cilium length and intraflagellar transport in renal " "epithelial cells.", "Regulation of cilium length and intraflagellar transport by the RCK-kinases ICK and MOK in renal epithelial cells.") PUGACHEVA = ev("PMID:17604723", "NEDD9/HEF1 activates Aurora A at the basal body, which phosphorylates and activates the " "tubulin deacetylase HDAC6 to drive ciliary disassembly.", "HEF1-dependent Aurora A activation induces disassembly of the primary cilium.") MIYAMOTO = ev("PMID:25660017", "PLK1-activated KIF2A depolymerizes microtubules at the basal body to drive primary cilium " "disassembly.", "The Microtubule-Depolymerizing Activity of a Mitotic Kinesin Protein KIF2A Drives Primary Cilia Disassembly " "Coupled with Cell Proliferation.") KINZEL = ev("PMID:20643351", "Pitchfork (CIMAP3) activates Aurora A at the basal body to regulate primary cilia disassembly.", "Pitchfork regulates primary cilia disassembly and left-right asymmetry.") TCTEX = ev("PMID:21394082", "Phosphorylated Tctex-1 (DYNLT1) at the transition zone controls ciliary resorption before " "S-phase entry.", "Ciliary transition zone activation of phosphorylated Tctex-1 controls ciliary resorption, S-phase entry and " "fate of neural progenitors.") KANIE = ev("PMID:39882855", "CEP89 positions myristoylated NCS1 at the distal appendages, where it captures preciliary " "vesicles for ciliary vesicle formation.") TTBK2_KIF2A = ev("PMID:39930500", "TTBK2 restrains the microtubule depolymerizer KIF2A at the mother centriole to " "support primary cilia growth.") HEF1_AURA = ev("PMID:16184168", "HEF1/NEDD9 activates Aurora A in vitro and is required for its activation at the " "centrosome.") ISMAIL = ev("PMID:22002721", "PDE6D is a GDI-like carrier for farnesylated cargo whose release is triggered by " "ARL2-GTP or ARL3-GTP.") WRIGHT = ev("PMID:22085962", "An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium.") KIF7_TIP = ev("PMID:24952464", "KIF7 organizes the cilium tip compartment by limiting microtubule growth at the tip.") MAK_RET = ev("PMID:39293864", "Ccrk-Mak/Ick signaling regulates ciliary transport and is essential for retinal " "photoreceptor survival.") RPGRIP1L_TZ = ev("PMID:26392567", "Mks5/RPGRIP1L is required to form the transition zone and its ciliary zone of " "exclusion.") MKS_NPHP = ev("PMID:21422230", "MKS and NPHP modules cooperate to establish basal body/transition zone membrane " "associations and ciliary gate function.") def part(order, role, node): return {"order": order, "role": role, "node": node} parts = [ part(1, "mother centriole licensing", { "id": "mother_centriole_licensing", "label": "Mother centriole licensing and basal body conversion", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:1905515")], "description": ( "The mother centriole becomes competent to template a cilium. Distal appendages, assembled in the order " "CEP83 then SCLT1 and CEP89 then FBF1 and CEP164, dock the centriole to membrane. CEP164 recruits TTBK2, " "which triggers removal of the CP110-CEP97 cap by phosphorylating cap-anchoring proteins (MPHOSPH9, " "CEP83); CP110 itself is not a known TTBK2 substrate. KIF24 recruits the cap and depolymerizes centriolar " "microtubules, restraining ciliogenesis in cycling cells. CEP89 also positions NCS1 to capture " "preciliary vesicles, linking this stage to ciliary vesicle formation. FBF1 is not needed for licensing " "itself (cap removal and TTBK2 recruitment are normal without it) but gates IFT and membrane-protein entry " "at the ciliary base."), "evidence": [TANOS, GOETZ, KOBAYASHI, KANIE], "annotons": [ annoton("distal_appendage_assembly", "Distal appendage (transition fiber) complex", complex_sel("centriole distal appendage complex", "Distal appendage proteins assembled hierarchically on the mother centriole.", ["CEP83", "SCLT1", "CEP89", "FBF1", "CEP164"], "distal appendage component"), "Docks the mother centriole to vesicles and membrane and recruits TTBK2.", fn_label="distal appendage scaffold", fn_desc=("Structural scaffold role; no specific GO molecular-function term is asserted. CEP89 " "additionally acts as an adaptor for NCS1-mediated vesicle capture."), processes=["GO:1905515"], locations=["GO:0036064"], evidence=[TANOS, KANIE]), annoton("ttbk2_cap_removal", "TTBK2 triggers CP110 cap removal", gp("TTBK2"), "Kinase recruited by CEP164 that triggers CP110-CEP97 cap removal and IFT recruitment, and " "restrains KIF2A during cilium growth.", fn="GO:0004674", processes=["GO:1905515"], locations=["GO:0036064"], evidence=[GOETZ, TTBK2_KIF2A]), annoton("cp110_cep97_cap", "CP110-CEP97 distal cap suppresses ciliogenesis", complex_sel("CP110-CEP97 distal centriole cap", "Cap on the distal end of the mother centriole that blocks axoneme extension until removed.", ["CCP110", "CEP97"], "distal cap component"), "Inhibitory cap; its removal licenses axoneme growth. CEP97 is the adaptor that stabilizes CP110.", fn_label="ciliogenesis suppressor cap", fn_desc="CP110 caps microtubule plus ends; CEP97 acts as a protein-macromolecule adaptor.", processes=["GO:1902018"], locations=["GO:0005814"], evidence=[KOBAYASHI, GOETZ]), annoton("kif24_cap_recruitment", "KIF24 recruits the cap and remodels centriolar microtubules", gp("KIF24"), "Kinesin-13 that recruits MPHOSPH9 and the CP110-CEP97 cap to the mother centriole and " "depolymerizes centriolar microtubules, suppressing ciliogenesis in cycling cells.", fn_label="microtubule depolymerase", fn_desc="No GO MF term for microtubule depolymerase activity.", processes=["GO:1902018"], locations=["GO:0005814"], evidence=[KOBAYASHI]), ], "connections": [ {"source": "distal_appendage_assembly", "target": "ttbk2_cap_removal", "connection_type": "PROVIDES_INPUT_FOR", "description": "CEP164 at the distal appendages recruits TTBK2 to the mother centriole."}, {"source": "ttbk2_cap_removal", "target": "cp110_cep97_cap", "connection_type": "NEGATIVELY_REGULATES", "description": "TTBK2 triggers removal of the CP110-CEP97 cap."}, {"source": "kif24_cap_recruitment", "target": "cp110_cep97_cap", "connection_type": "POSITIVELY_REGULATES", "description": "KIF24 recruits and maintains the cap at the mother centriole."}, ], }), part(2, "ciliary vesicle formation", { "id": "ciliary_vesicle_formation", "label": "Ciliary vesicle formation at the distal appendages", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:1905556")], "description": ( "Myosin-Va delivers preciliary vesicles to the distal appendages, upstream of ciliary vesicle formation. " "EHD1 and EHD3 tubulate the docked distal appendage vesicles so they fuse into a single ciliary vesicle; " "EHD1 is the dominant paralog in RPE1 cells. CEP290 also acts here, at centriolar satellites, in ciliary " "vesicle maturation and RAB8A recruitment."), "evidence": [WU, LU], "annotons": [ annoton("myo5a_vesicle_delivery", "Myosin-Va preciliary vesicle delivery", gp("MYO5A"), "Processive actin motor that carries preciliary vesicles to the mother centriole; its dominant " "roles (melanosome and secretory vesicle transport) lie outside cilia.", fn="GO:0000146", processes=["GO:0030050", "GO:0060271"], evidence=[WU]), annoton("ehd_vesicle_tubulation", "EHD1/EHD3 membrane tubulation", complex_sel("EHD1/EHD3 membrane-shaping proteins", "Membrane-tubulating EH-domain ATPases acting on distal appendage vesicles.", ["EHD1", "EHD3"], "membrane-shaping ATPase"), "Tubulate distal appendage vesicles to form the ciliary vesicle.", fn="GO:0016887", fn_label="ATP hydrolysis activity", processes=["GO:1905556"], locations=["GO:0097721"], evidence=[LU]), ], "connections": [ {"source": "myo5a_vesicle_delivery", "target": "ehd_vesicle_tubulation", "connection_type": "PRECEDES", "description": "Delivered vesicles are remodeled by EHD1/EHD3 into the ciliary vesicle."}, ], }), part(3, "ciliary membrane extension", { "id": "ciliary_membrane_extension", "label": "Ciliary membrane supply and extension", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:0060271")], "description": ( "Once the ciliary vesicle has formed, the RAB11-Rabin8-RAB8 cascade supplies membrane for the growing " "ciliary sheath; RAB8 is activated only after ciliary vesicle assembly. RAB8A is pleiotropic and also acts " "in exocytosis and endocytic recycling."), "evidence": [NACHURY, LU], "annotons": [ annoton("rabin8_rab8_gef", "Rabin8 activates Rab8", gp("RAB3IP"), "RAB8 guanine nucleotide exchange factor, delivered to the mother centriole downstream of RAB11.", fn="GO:0005085", processes=["GO:0060271"], evidence=[NACHURY]), annoton("rab8_membrane_supply", "Rab8 ciliary membrane delivery", gp("RAB8A"), "GTP-bound RAB8A enters the cilium and promotes ciliary membrane extension.", fn="GO:0003924", processes=["GO:0060271"], locations=["GO:0060170"], evidence=[NACHURY, LU]), ], "connections": [ {"source": "rabin8_rab8_gef", "target": "rab8_membrane_supply", "connection_type": "POSITIVELY_REGULATES", "description": "Rabin8 loads RAB8A with GTP."}, ], }), part(4, "transition zone assembly", { "id": "transition_zone_assembly", "label": "Transition zone assembly", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:1905349")], "description": ( "The transition zone forms between basal body and axoneme and gates ciliary membrane composition. " "RPGRIP1L acts upstream as the foundational assembly factor for both the MKS and NPHP modules and CEP290. " "In the NPHP module, NPHP4 is the adaptor hub bridging RPGRIP1L and NPHP1; NPHP1 depends on both to reach " "the transition zone. MKS1-B9D2-B9D1 form a linear core of the MKS module. CEP290 is its own transition " "zone component, not an MKS subunit. GO has merged the former basal body-plasma membrane docking and " "transition fiber assembly terms into this process."), "evidence": [GARCIA, RPGRIP1L_TZ, MKS_NPHP], "annotons": [ annoton("rpgrip1l_tz_foundation", "RPGRIP1L founds the transition zone", gp("RPGRIP1L"), "Foundational transition zone assembly factor upstream of the MKS and NPHP modules and CEP290.", fn_label="transition zone scaffold", processes=["GO:1905349"], locations=["GO:0035869"], evidence=[RPGRIP1L_TZ]), annoton("mks_module", "MKS module", complex_sel("MKS complex", "Tectonic/MKS ciliopathy protein complex at the transition zone.", ["MKS1", "TMEM67", "CC2D2A", "B9D1", "B9D2", "TCTN1", "TCTN2", "TMEM216", "TMEM231"], "MKS module component", "GO:0036038"), "Transition zone gate that controls entry of ciliary membrane proteins.", fn_label="ciliary diffusion barrier", fn_desc="Barrier/gating role; no GO MF term asserted.", processes=["GO:1905349"], locations=["GO:0035869"], evidence=[GARCIA]), annoton("nphp_module", "NPHP module", complex_sel("NPHP module", "Nephronophthisis proteins at the transition zone; NPHP4 is the hub.", ["NPHP4", "NPHP1"], "NPHP module component"), "Second transition zone module, partly redundant with the MKS module.", fn="GO:0030674", processes=["GO:1905349"], locations=["GO:0035869"], evidence=[MKS_NPHP]), annoton("cep290_tz_scaffold", "CEP290 transition zone scaffold", gp("CEP290"), "Builds the microtubule-to-membrane Y-links of the transition zone; also acts at centriolar " "satellites in ciliary vesicle maturation.", fn_label="transition zone scaffold", processes=["GO:1905349"], locations=["GO:0035869"], evidence=[GARCIA]), ], "connections": [ {"source": "rpgrip1l_tz_foundation", "target": "mks_module", "connection_type": "PRECEDES", "description": "RPGRIP1L is required to assemble the MKS module."}, {"source": "rpgrip1l_tz_foundation", "target": "nphp_module", "connection_type": "PRECEDES", "description": "RPGRIP1L is required to recruit the NPHP module."}, {"source": "rpgrip1l_tz_foundation", "target": "cep290_tz_scaffold", "connection_type": "PRECEDES", "description": "RPGRIP1L is required for CEP290 localization."}, ], }), part(5, "axoneme extension by IFT", { "id": "axoneme_extension_ift", "label": "Axoneme extension by intraflagellar transport", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:0042073")], "description": ( "IFT trains carry axoneme precursors and membrane proteins to the ciliary tip and back. Kinesin-2 " "(KIF3A/KIF3B motors with the KIFAP3 cargo adaptor) drives anterograde trains carrying IFT-B. Within " "IFT-B, IFT81-IFT74 bind tubulin cargo, and IFT88, IFT52 and IFT172 are scaffolds. Dynein-2 drives " "retrograde trains. IFT-A acts in retrograde transport and, with TULP3, imports membrane proteins; loss " "of IFT-A subunits other than IFT122 has only mild effects on ciliogenesis."), "evidence": [PAZOUR, TASCHNER, IFTA, TOROPOVA], "annotons": [ annoton("ift_b_scaffold", "IFT-B scaffold subunits", complex_sel("IFT-B complex (scaffold subunits)", "Structural core and peripheral IFT-B subunits.", ["IFT88", "IFT52", "IFT172"], "IFT-B subunit", "GO:0030992"), "Backbone of anterograde IFT trains.", fn_label="IFT-B structural scaffold", fn_desc="No GO MF term asserted; cargo binding is shown only for IFT81-IFT74.", processes=["GO:0035720", "GO:0060271"], locations=["GO:0097730"], evidence=[PAZOUR, TASCHNER]), annoton("ift81_ift74_tubulin", "IFT81-IFT74 tubulin module", complex_sel("IFT81-IFT74 tubulin-binding module", "IFT-B subcomplex that binds tubulin cargo.", ["IFT81", "IFT74"], "tubulin-binding IFT-B subunit", "GO:0030992"), "Binds tubulin for delivery to the growing axoneme tip.", fn="GO:0015631", processes=["GO:0035720", "GO:0060271"], locations=["GO:0097730"], evidence=[TASCHNER]), annoton("ift_a_complex", "IFT-A complex", complex_sel("IFT-A complex", "Retrograde IFT and membrane-protein import complex.", ["IFT140", "IFT122", "WDR35", "TTC21B"], "IFT-A subunit", "GO:0030991"), "Retrograde train component and, with TULP3, carrier for membrane-protein entry into cilia.", fn="GO:0140597", processes=["GO:0035721", "GO:0061512"], locations=["GO:0097730"], evidence=[IFTA, TULP3]), annoton("kinesin2_anterograde", "Heterotrimeric kinesin-2", kinesin2_sel(), "Anterograde IFT motor. KIF3A and KIF3B carry the motor activity; KIFAP3 contributes to it as " "the non-motor cargo adaptor (protein-macromolecule adaptor activity).", fn="GO:0008574", processes=["GO:0035720"], locations=["GO:0005930"]), annoton("dynein2_retrograde", "Dynein-2", complex_sel("cytoplasmic dynein-2", "Retrograde IFT motor complex; DYNC2H1 is the motor, the " "intermediate and light intermediate chains contribute.", ["DYNC2H1", "DYNC2LI1", "DYNC2I1", "DYNC2I2"], "dynein-2 subunit", "GO:0005868"), "Retrograde IFT motor, carried to the tip in an autoinhibited state on anterograde trains.", fn="GO:0008569", processes=["GO:0035721"], locations=["GO:0005930"], evidence=[TOROPOVA]), ], "connections": [ {"source": "kinesin2_anterograde", "target": "ift_b_scaffold", "connection_type": "PROVIDES_INPUT_FOR", "description": "Kinesin-2 moves IFT-B trains toward the ciliary tip."}, {"source": "dynein2_retrograde", "target": "ift_a_complex", "connection_type": "PROVIDES_INPUT_FOR", "description": "Dynein-2 returns IFT-A trains to the base."}, ], }), part(6, "ciliary membrane composition", { "id": "ciliary_membrane_composition", "label": "Ciliary membrane identity and protein targeting", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:0061512")], "description": ( "Mature cilia keep a distinct membrane. ARL13B activates ARL3, a GTP-dependent switch whose GTP-bound form " "releases lipidated cargo from PDE6D (farnesylated/prenylated cargo) and UNC119B (myristoylated cargo) " "inside the cilium; RP2 inactivates ARL3. INPP5E keeps PI(4,5)P2 low in the ciliary membrane, and TULP3 " "couples IFT-A to phosphoinositides to import GPCRs. PDE6D also solubilizes farnesylated RAS outside " "cilia. BBSome-mediated export is modeled in modules/bbsome.yaml."), "evidence": [GOTTHARDT, TULP3, INPP5E_EV, ISMAIL, WRIGHT], "annotons": [ annoton("arl13b_arl3_gef", "ARL13B activates ARL3", gp("ARL13B"), "Ciliary membrane GTPase that acts as GEF for ARL3.", fn="GO:0005085", processes=["GO:0061512"], locations=["GO:0060170"], evidence=[GOTTHARDT]), annoton("arl3_cargo_release", "ARL3 releases lipidated cargo", gp("ARL3"), "ARL3-GTP binds PDE6D and UNC119B and displaces their lipidated cargo inside the cilium; its intrinsic " "GTP hydrolysis is negligible without RP2.", fn="GO:0003925", processes=["GO:1903441"], evidence=[GOTTHARDT]), annoton("pde6d_prenyl_carrier", "PDE6D carries farnesylated cargo", gp("PDE6D"), "GDI-like carrier for farnesylated and prenylated cargo such as INPP5E and PDE6 subunits.", fn="GO:0001918", processes=["GO:0061512"], evidence=[ISMAIL]), annoton("unc119b_myristoyl_carrier", "UNC119B carries myristoylated cargo", gp("UNC119B"), "Binds the myristoyl group of cargo such as NPHP3 and delivers it to the ciliary membrane.", fn="GO:0008289", processes=["GO:1903441"], evidence=[WRIGHT]), annoton("rp2_arl3_gap", "RP2 inactivates ARL3", gp("RP2"), "GTPase-activating protein for ARL3; a regulator, not a cargo carrier.", fn="GO:0005096", processes=["GO:1903441"], evidence=[WRIGHT]), annoton("inpp5e_pip2_hydrolysis", "INPP5E sets ciliary phosphoinositides", gp("INPP5E"), "Hydrolyzes PI(4,5)P2 (and PI(3,4,5)P3) in the ciliary membrane.", fn="GO:0004439", locations=["GO:0060170"], evidence=[INPP5E_EV]), annoton("tulp3_gpcr_import", "TULP3 links IFT-A to membrane cargo", gp("TULP3"), "Adaptor bridging IFT-A and phosphoinositides for GPCR import.", fn="GO:0030674", processes=["GO:0061512"], evidence=[TULP3]), ], "connections": [ {"source": "arl13b_arl3_gef", "target": "arl3_cargo_release", "connection_type": "POSITIVELY_REGULATES", "description": "ARL13B loads ARL3 with GTP."}, {"source": "rp2_arl3_gap", "target": "arl3_cargo_release", "connection_type": "NEGATIVELY_REGULATES", "description": "RP2 stimulates ARL3 GTP hydrolysis."}, {"source": "pde6d_prenyl_carrier", "target": "arl3_cargo_release", "connection_type": "PROVIDES_INPUT_FOR", "description": "PDE6D-bound cargo is released by ARL3-GTP."}, {"source": "unc119b_myristoyl_carrier", "target": "arl3_cargo_release", "connection_type": "PROVIDES_INPUT_FOR", "description": "UNC119B-bound cargo is released by ARL3-GTP."}, ], }), part(7, "length control", { "id": "cilium_length_control", "label": "Cilium length control", "module_type": "REGULATORY_STEP", "concepts": [concept("GO:1902856")], "description": ( "Steady-state length reflects the balance of assembly and turnover at the tip. The RCK kinases CILK1 and " "MAK limit length by regulating IFT turnaround; CILK1 is the better-supported length kinase in most cells, " "while MAK evidence comes mainly from the photoreceptor connecting cilium. KIF7, a non-motile kinesin-4, " "binds growing microtubule plus ends and slows their growth at the tip. GO has no cilium-length term, so " "negative regulation of non-motile cilium assembly is used."), "evidence": [ICK, ICK_MOK, MAK_RET, KIF7_TIP], "annotons": [ annoton("rck_kinases", "RCK kinases restrict cilium length", complex_sel("RCK kinases", "Ciliary length-control kinases (not a stable complex).", ["CILK1", "MAK"], "length-control kinase"), "Phosphorylate kinesin-2 and IFT components to control IFT turnaround and length.", fn="GO:0004674", processes=["GO:1902856"], locations=["GO:0097542"], evidence=[ICK, ICK_MOK, MAK_RET]), annoton("kif7_tip_organizer", "KIF7 limits microtubule growth at the tip", gp("KIF7"), "Non-motile kinesin-4 that binds microtubule plus ends at the ciliary tip and slows their growth; " "also a core Hedgehog-pathway regulator.", fn="GO:0051010", processes=["GO:0031115", "GO:1902856"], locations=["GO:0097542"], evidence=[KIF7_TIP]), ], }), part(8, "cilium disassembly", { "id": "cilium_disassembly", "label": "Cilium disassembly before cell-cycle re-entry", "module_type": "BIOLOGICAL_PROCESS", "concepts": [concept("GO:0061523")], "description": ( "On cell-cycle re-entry the cilium is resorbed so the centrioles can act at the spindle poles. NEDD9 and " "Pitchfork (CIMAP3) activate Aurora A at the basal body; Aurora A activates the tubulin deacetylase " "HDAC6. PLK1 activates KIF2A, which depolymerizes microtubules at the base and is held back by TTBK2 " "while the cilium grows. Phosphorylated Tctex-1 (DYNLT1) at the transition zone promotes resorption " "independently of dynein. AURKA, PLK1, KIF2A and NEDD9 are pleiotropic: their dominant roles are mitotic " "or adhesion-related, and ciliary disassembly is a secondary function."), "evidence": [PUGACHEVA, MIYAMOTO, KINZEL, TCTEX, HEF1_AURA, TTBK2_KIF2A], "annotons": [ annoton("aurka_disassembly_kinase", "Aurora A drives disassembly", gp("AURKA"), "Basal body kinase activated by NEDD9 and Pitchfork; phosphorylates HDAC6.", fn="GO:0004674", processes=["GO:0061523"], locations=["GO:0036064"], evidence=[PUGACHEVA]), annoton("nedd9_aurka_activation", "NEDD9 activates Aurora A", gp("NEDD9"), "Cas-family scaffold that activates Aurora A at the basal body.", fn="GO:0043539", processes=["GO:0061523"], evidence=[PUGACHEVA, HEF1_AURA]), annoton("pitchfork_aurka_activation", "Pitchfork activates Aurora A", gp("CIMAP3"), "Activates Aurora A at the basal body to drive cilium disassembly.", fn="GO:0030295", processes=["GO:0061523"], evidence=[KINZEL]), annoton("hdac6_deacetylation", "HDAC6 deacetylates axonemal tubulin", gp("HDAC6"), "Tubulin deacetylase activated by Aurora A.", fn="GO:0042903", processes=["GO:0061523"], evidence=[PUGACHEVA]), annoton("plk1_kinase", "PLK1 activates KIF2A", gp("PLK1"), "Kinase that activates KIF2A at the basal body.", fn="GO:0004674", processes=["GO:0061523"], evidence=[MIYAMOTO]), annoton("kif2a_depolymerization", "KIF2A depolymerizes microtubules", gp("KIF2A"), "Kinesin-13 ATP-dependent microtubule depolymerase acting at the mother centriole.", fn_label="ATP-dependent microtubule depolymerase activity", fn_desc="No GO MF term exists; proposed as a new term in the KIF2A review.", processes=["GO:0007019", "GO:0061523"], locations=["GO:0036064"], evidence=[MIYAMOTO, TTBK2_KIF2A]), annoton("tctex1_resorption", "Phosphorylated Tctex-1 promotes resorption", gp("DYNLT1"), "Phospho-Tctex-1 at the transition zone promotes ciliary resorption, independently of dynein.", fn_label="resorption promoter", processes=["GO:0061523"], locations=["GO:0035869"], evidence=[TCTEX]), ], "connections": [ {"source": "nedd9_aurka_activation", "target": "aurka_disassembly_kinase", "connection_type": "POSITIVELY_REGULATES", "description": "NEDD9 activates Aurora A."}, {"source": "pitchfork_aurka_activation", "target": "aurka_disassembly_kinase", "connection_type": "POSITIVELY_REGULATES", "description": "Pitchfork activates Aurora A."}, {"source": "aurka_disassembly_kinase", "target": "hdac6_deacetylation", "connection_type": "POSITIVELY_REGULATES", "description": "Aurora A phosphorylates and activates HDAC6."}, {"source": "plk1_kinase", "target": "kif2a_depolymerization", "connection_type": "POSITIVELY_REGULATES", "description": "PLK1 activates KIF2A."}, ], }), ] doc = { "id": "MODULE:primary_cilium_life_cycle", "title": "Primary cilium life cycle module", "description": ( "The primary cilium is a microtubule-based sensory organelle templated by the mother centriole. Its life " "cycle runs from licensing of the mother centriole as a basal body, through ciliary vesicle formation, " "transition zone assembly and IFT-driven axoneme extension, to maintenance of a distinct ciliary membrane, " "control of cilium length, and disassembly when the cell re-enters the cell cycle. This module captures the " "ordered stages and the protein roles that carry out each stage, using human proteins as concrete members."), "status": "DRAFT", "scope": "CONCRETE", "evidence": [ {**HPA_ATLAS, "statement": ( "HPA primary-cilium atlas: antibody-based sub-ciliary localization of 715 proteins in three cell lines. " "Used here as localization evidence for module members; most calls are graded Approved or Uncertain.")}, TANOS, GOETZ, LU, GARCIA, TOROPOVA, PUGACHEVA, MIYAMOTO, ], "notes": ( "Revised 2026-10-03 after gene reviews of all 60 members (genes/human//). " "Draft built in the HUMAN_PROTEIN_ATLAS project. Members and UniProt accessions come from " "projects/HUMAN_PROTEIN_ATLAS/cilium_life_cycle/candidate_members.yaml (UniProt REST). Several roles have no " "GO molecular-function term (distal appendage scaffold, transition zone barrier, IFT adaptor, microtubule " "depolymerase) and carry preferred_term only. BBSome cargo export is a separate module (modules/bbsome.yaml). " "Motile cilia, centriole duplication and the ciliary pocket are outside this boundary. " "Ontology gaps: GO has no term for regulation of cilium length (negative regulation of non-motile cilium " "assembly is used), no cytoplasmic dynein-2 complex term (the generic cytoplasmic dynein complex is used) and " "no microtubule depolymerase activity term (KIF2A, KIF24); these are candidate GO term requests. Curation " "note: many members have only Approved or Uncertain HPA cilium-atlas calls, which are not exported to GOA; " "whether those calls should become annotations is tracked in the HUMAN_PROTEIN_ATLAS project."), "module": { "id": "primary_cilium_life_cycle", "label": "Primary cilium life cycle", "module_type": "ORGANELLE_LIFECYCLE", "concepts": [ concept("GO:0044782", "Assembly, arrangement and disassembly of a cilium."), concept("GO:0097730"), ], "context": { "taxa": [{"preferred_term": "Homo sapiens", "term": {"id": "NCBITaxon:9606", "label": "Homo sapiens"}}], "conditions": [{"preferred_term": "quiescent or differentiated cells that form a primary cilium", "description": "Cilia assemble in G0/G1 and are resorbed before mitosis."}], }, "parts": parts, "connections": [ {"source": "mother_centriole_licensing", "target": "ciliary_vesicle_formation", "connection_type": "PRECEDES"}, {"source": "ciliary_vesicle_formation", "target": "ciliary_membrane_extension", "connection_type": "PRECEDES", "description": "RAB8 is activated only after the ciliary vesicle has formed."}, {"source": "ciliary_vesicle_formation", "target": "transition_zone_assembly", "connection_type": "PRECEDES"}, {"source": "transition_zone_assembly", "target": "axoneme_extension_ift", "connection_type": "PRECEDES"}, {"source": "axoneme_extension_ift", "target": "ciliary_membrane_composition", "connection_type": "PRECEDES"}, {"source": "ciliary_membrane_composition", "target": "cilium_disassembly", "connection_type": "PRECEDES", "description": "A mature cilium is resorbed when the cell re-enters the cell cycle."}, {"source": "cilium_length_control", "target": "axoneme_extension_ift", "connection_type": "NEGATIVELY_REGULATES", "description": "RCK kinases and KIF7 limit axoneme length."}, ], }, "knowledge_gaps": [ {"gap_statement": ("The molecular activities of the distal appendage proteins (CEP83, SCLT1, FBF1, CEP164), " "the transition zone MKS-module proteins and the IFT-B scaffold subunits (IFT88, IFT52, " "IFT172) are unknown beyond 'structural scaffold'."), "boundary": ("Their requirement for ciliogenesis and their positions are well established; what each " "protein does mechanistically (binding partners, membrane contacts, gating chemistry) is not."), "gap_kind": ["BIOLOGY"], "status": "OPEN", "significance": ("Most structural ciliogenesis proteins have no defined molecular function, so the module " "can say where they act but not how."), "resolution": ("Reconstitution and structure-function work, for example in vitro membrane-binding and " "barrier assays with purified MKS-module and distal appendage subcomplexes.")}, ], } class Dumper(yaml.SafeDumper): pass def str_presenter(dumper, data): if len(data) > 100: return dumper.represent_scalar("tag:yaml.org,2002:str", data, style=">") return dumper.represent_scalar("tag:yaml.org,2002:str", data) Dumper.add_representer(str, str_presenter) OUT.write_text(yaml.dump(doc, Dumper=Dumper, sort_keys=False, width=100, allow_unicode=True)) print(f"wrote {OUT}")