Affinage

Showing SNAP91 — AP180 is a alias.

SNAP91

Clathrin coat assembly protein AP180 · UniProt O60641

Length
907 aa
Mass
92.5 kDa
Annotated
2026-06-10
56 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNAP91 (AP180) is a neuron-enriched monomeric clathrin assembly protein that nucleates clathrin coat formation during synaptic vesicle endocytosis and selects vesicle cargo, organized into an N-terminal ANTH domain and an acidic, intrinsically disordered C-terminal assembly domain (PMID:8440257, PMID:11756460). It drives polymerization of clathrin triskelia into homogeneous coated structures in vitro (PMID:3191110, PMID:8440257), binding clathrin heavy chains directly through a conserved C-terminal motif independently of light chains (PMID:1909890, PMID:27574975). Its ANTH domain anchors the protein to PtdIns(4,5)P2-rich membranes through a lysine-rich motif and pH-sensitive histidine residues, allowing AP180 to simultaneously tether clathrin to the membrane; together with AP-2 it nucleates clathrin lattice and coated pit formation on lipid monolayers (PMID:11161218, PMID:17825837, PMID:10428863). The disordered C-terminal region carries the primary high-affinity AP-2 binding site, and casein kinase II phosphorylation weakens AP-2 binding and inhibits clathrin assembly, providing a regulatory switch reversed by activity-dependent calcineurin dephosphorylation (PMID:10428863, PMID:39003270, PMID:11145983, PMID:31129113). The ANTH domain also acts as a cargo-specific adaptor, directly recognizing the SNARE motif of synaptobrevin 2/VAMP2 around residue M46 to ensure selective retrieval of synaptobrevin into newly forming vesicles, a cargo-selection function conserved across model organisms (PMID:21808019, PMID:10397769, PMID:19692567). The assembly domain further forms condensates that enrich actin monomers and nucleate filament assembly, coupling PtdIns(4,5)P2 membranes to actin to set vesicle size (PMID:41650190). Loss of AP180 in C. elegans, Drosophila, and mice mislocalizes synaptic vesicle proteins, enlarges vesicles, impairs endocytic membrane retrieval and vesicle reformation, and causes defective neurotransmission, excitatory/inhibitory imbalance, seizures, and hearing impairment in vivo (PMID:10397769, PMID:15888532, PMID:26412491, PMID:31843760).

Mechanistic history

Synthesis pass · year-by-year structured walk · 31 steps
  1. 1988 High

    Established that the brain coated-vesicle protein AP180 is itself an active clathrin assembly factor, defining its core biochemical activity.

    Evidence Biochemical purification from bovine brain with sedimentation equilibrium, CD, and in vitro clathrin assembly

    PMID:3191110

    Open questions at the time
    • Did not map which protein region drives assembly
    • Membrane and cargo context not addressed
  2. 1993 High

    Defined the three-domain architecture and localized the clathrin binding site to the N-terminal region, providing the structural framework for mechanism.

    Evidence cDNA cloning, proteolytic mapping, in vitro assembly assay

    PMID:8440257

    Open questions at the time
    • Atomic structure of domains not resolved
    • Regulatory inputs unknown
  3. 1991 Medium

    Showed AP180 binds clathrin heavy chains directly and independent of light chains, simplifying the assembly mechanism.

    Evidence In vitro clathrin reassembly and immunoblotting

    PMID:1909890

    Open questions at the time
    • Single study/lab
    • Precise heavy-chain contact residues not mapped
  4. 1995 High

    Revealed that inositol polyphosphate ligands negatively regulate AP180 assembly activity, introducing the concept of phosphoinositide control.

    Evidence Affinity chromatography and quantitative in vitro binding/assembly assays with InsP6

    PMID:7814377

    Open questions at the time
    • Physiological lipid ligand on membranes not yet identified
    • In vivo relevance untested
  5. 1999 High

    Demonstrated direct AP180-AP-2 cooperation and CK2 phosphorylation as a regulatory switch, linking assembly to a kinase-controlled mechanism.

    Evidence In vitro binding, cooperative assembly, CK2 phosphorylation, and domain mapping

    PMID:10428863

    Open questions at the time
    • In vivo phosphosites and kinase specificity incompletely resolved
    • Cellular consequence of weakened binding not directly measured
  6. 1999 High

    Provided in vivo loss-of-function proof that the AP180 assembly domain is required for synaptic vesicle endocytosis.

    Evidence Microinjection of domains/peptides into squid giant synapse with electrophysiology and EM

    PMID:10575017

    Open questions at the time
    • Cargo selectivity not addressed
    • Did not distinguish coat nucleation from cargo recruitment
  7. 1999 High

    Genetic ablation of the AP180 ortholog UNC-11 established its role in recruiting synaptobrevin and controlling vesicle size in vivo.

    Evidence C. elegans genetics with immunolocalization and EM

    PMID:10397769

    Open questions at the time
    • Direct binding to synaptobrevin not demonstrated here
    • Molecular basis of size control unknown
  8. 2001 High

    Resolved the ANTH domain structure bound to PtdIns(4,5)P2 and reconstituted membrane-tethered coated pit formation, unifying membrane recognition with assembly.

    Evidence X-ray crystallography of CALM ANTH plus lipid monolayer budding with purified components

    PMID:11161218

    Open questions at the time
    • Crystal structure was of the CALM homolog
    • Dynamics of AP180-AP-2-clathrin assembly not captured
  9. 2001 Medium

    Established that the clathrin assembly domain is intrinsically disordered, framing how a flexible chain organizes the coat.

    Evidence Hydrodynamic and CD analysis with in vitro assembly

    PMID:11756460

    Open questions at the time
    • How disorder mediates binding not mechanistically resolved
    • Single lab
  10. 2001 Medium

    Overexpression clathrin-sequestration assays confirmed clathrin binding is functionally rate-limiting for endocytosis in cells.

    Evidence Cellular overexpression with transferrin uptake and immunofluorescence

    PMID:11148137

    Open questions at the time
    • Overexpression artifact possible
    • Neuronal context not tested
  11. 2001 Medium

    Identified AP180 as a calcineurin-dephosphorylated 'dephosphin' acting in activity-dependent endocytosis, distinguishing its kinase regulation from dynamin/synaptojanin.

    Evidence Synaptosomal phosphorylation assays with kinase pharmacology and depolarization

    PMID:11145983

    Open questions at the time
    • Rephosphorylating kinase not identified
    • Functional consequence of cycle not directly tested
  12. 2002 Medium

    Ultrastructural localization placed AP180 at the cytosolic presynaptic membrane and ribbon synapses, matching its endocytic role.

    Evidence Immunoelectron microscopy of rat cerebellum and primate retina

    PMID:11977118

    Open questions at the time
    • Single localization study
    • Dynamic relocalization during activity not captured
  13. 2002 High

    Genetic epistasis placed AP180 downstream of ubiquitin signaling in glutamate receptor endocytosis, extending its cargo range beyond vesicle SNAREs.

    Evidence C. elegans epistasis with GFP reporter imaging and behavior

    PMID:12123612

    Open questions at the time
    • Direct receptor binding not shown
    • Mammalian conservation untested
  14. 2002 Medium

    Identified non-endocytic AP180 interactions with PLCγ1 and microtubule tubulin, hinting at signaling/cytoskeletal links.

    Evidence Brain pulldowns, co-IP, enzyme activity and binding assays

    PMID:11779129 PMID:12750376

    Open questions at the time
    • Physiological significance unclear
    • Single-study interactions, not reciprocally validated in vivo
  15. 2005 High

    Drosophila LAP deletion showed AP180 maintains synaptic localization of multiple vesicle proteins and couples calcium to release, broadening its in vivo role.

    Evidence Drosophila deletion genetics with electrophysiology, immunocytochemistry, EM, imaging

    PMID:15888532

    Open questions at the time
    • Direct cargo binding not demonstrated
    • Mechanism of calcium-coupling defect unresolved
  16. 2007 High

    Defined pH-dependent histidine protonation as a tunable mechanism for ANTH-PtdIns(4,5)P2 membrane anchoring.

    Evidence Liposome binding, SPR, NMR, monolayer tension, mutagenesis

    PMID:17825837

    Open questions at the time
    • In vivo relevance of pH switch untested
    • Coupling to coat assembly not directly shown
  17. 2008 Medium

    Knockdown showed AP180 is required for endocytosis and axonal development, distinguishing its trafficking role from CALM.

    Evidence RNAi in hippocampal neurons with live imaging and transferrin uptake

    PMID:18842885

    Open questions at the time
    • Molecular basis of axon-specific phenotype unclear
    • Off-target RNAi not fully excluded
  18. 2009 Medium

    Cross-species and cell-line studies extended AP180 SNARE-cargo selection to Dictyostelium Vamp7B and linked AP180 to APP processing.

    Evidence Dictyostelium knockout with in vitro binding; RNAi with Aβ ELISA

    PMID:19450545 PMID:19692567

    Open questions at the time
    • APP cargo mechanism not defined
    • Single-lab assays each
  19. 2011 High

    Resolved that the ANTH domain directly reads the synaptobrevin 2 SNARE motif around M46, defining AP180 as a cargo-specific endocytic adaptor.

    Evidence NMR, site-directed mutagenesis, neuronal knockdown with selective surface-cargo assay

    PMID:21808019

    Open questions at the time
    • Stoichiometry within the coat not resolved
    • How cargo binding integrates with PtdIns(4,5)P2 binding unclear
  20. 2011 Medium

    Mapped a TSP/Ser313 motif required for AP180 binding and inhibition of PLD1 (but not PLD2), adding isoform-specific lipid-signaling regulation.

    Evidence Overexpression, deletion mutagenesis, PLD activity and binding assays

    PMID:21296491

    Open questions at the time
    • Physiological/neuronal relevance untested
    • Single study
  21. 2012 Medium

    Confirmed in mammalian neurons that AP180 loss enlarges synaptic vesicles and reduces vesicle cluster density, linking it to vesicle size control.

    Evidence RNAi in hippocampal neurons with fluorescence and EM

    PMID:22851330

    Open questions at the time
    • Mechanism of size control not identified here
    • Single lab
  22. 2014 High

    Acute Drosophila inactivation showed AP180 maintains vesicle protein complex integrity at the membrane during recycling, with co-IP of vesicle cargo.

    Evidence Drosophila genetics, FM 1-43 uptake, EM, co-IP

    PMID:24456281

    Open questions at the time
    • Direct versus indirect cargo association unresolved
    • Mammalian conservation of complex-maintenance role untested
  23. 2015 High

    AP180 knockout mice established that AP180 maintains a vesicular synaptobrevin 2 pool essential for neurotransmission, with seizures and lethality, proving physiological necessity.

    Evidence Knockout mouse, patch-clamp, immunostaining, AP180−/−/Syb2+/− epistasis

    PMID:26412491

    Open questions at the time
    • Cell-type-specific contributions not dissected here
    • Link to human disease not established
  24. 2016 Medium

    Identified the conserved LDSSLA[S/N]LVGNLGI sequence in the C-terminal subdomain as the major clathrin interaction site, refining the assembly mechanism.

    Evidence In vitro clathrin binding/assembly, mutagenesis, transferrin uptake

    PMID:27574975

    Open questions at the time
    • Discrepancy between isolated-peptide and full-length DL(L/F) motif behavior unresolved
    • Structural basis of the contact not solved
  25. 2019 Medium

    Phospho-mimetic mutagenesis supported a model where AP180 phosphorylation inhibits clathrin binding and assembly, mechanistically completing the regulatory switch.

    Evidence Site-directed mutagenesis with in vitro clathrin binding/assembly

    PMID:31129113

    Open questions at the time
    • Phospho-mimetic may not reproduce true phosphorylation
    • In vivo phosphosites not validated
  26. 2020 High

    Cochlear hair cell knockouts showed AP180 drives clathrin-dependent vesicle reformation and release-site clearance, extending its role to sensory synapses and hearing.

    Evidence Knockout mouse, electron tomography, patch-clamp capacitance, ABR

    PMID:31843760

    Open questions at the time
    • Molecular basis of multi-tethered SV accumulation unresolved
    • Cargo-selection contribution at ribbon synapses not isolated
  27. 2021 Medium

    Identified docosahexaenoyl-phosphatidic acid as a lipid that weakens AP180-clathrin interaction, revealing a lipid-driven coat disassembly mechanism distinct from PtdIns(4,5)P2.

    Evidence Liposome binding, domain mapping, mutagenesis, clathrin interaction assay

    PMID:34864549

    Open questions at the time
    • In vivo role of PA in coat dynamics untested
    • Single lab
  28. 2023 Medium

    Showed α-synuclein cooperates with AP180 at clathrin puncta to enlarge clathrin lattices, connecting AP180 to a Parkinson-associated protein in coat-size regulation.

    Evidence Super-resolution imaging, lipid monolayer assembly, immunoEM of synaptosomes

    PMID:37516240

    Open questions at the time
    • Direct AP180-α-synuclein binding not established
    • Functional consequence for endocytosis not measured
  29. 2024 High

    Atomic-resolution NMR mapped an extended ~70-residue primary AP-2 binding site in the IDR operating in dynamic equilibrium, refining the AP180-AP-2 interaction.

    Evidence NMR spectroscopy and binding dynamics analysis

    PMID:39003270

    Open questions at the time
    • Structural model within the assembled coat not built
    • Functional impact of dynamic equilibrium untested in cells
  30. 2024 Low

    Synaptosomal proteomics detected calcium-triggered changes in AP180 ubiquitination, hinting at activity-dependent post-translational regulation.

    Evidence Quantitative ubiquitination mass spectrometry of resting versus stimulated synaptosomes (preprint)

    PMID:bio_10.1101_2024.07.04.602026

    Open questions at the time
    • Single MS dataset from a preprint
    • No mutagenesis or functional follow-up for AP180
    • Ubiquitin sites and consequences unknown
  31. 2026 High

    Established that the intrinsically disordered assembly domain forms actin-enriching condensates that couple PtdIns(4,5)P2 membranes to actin assembly to set vesicle size, providing a mechanism for AP180's size-control function.

    Evidence C. elegans genetics with domain-swap rescue, in vitro condensate/actin assays, electrophysiology, EM

    PMID:41650190

    Open questions at the time
    • Mammalian conservation of condensate mechanism untested
    • How actin organization couples to clathrin coat geometry unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AP180's separable functions—membrane anchoring, clathrin nucleation, cargo (synaptobrevin) selection, and actin-coupled size control—are integrated and temporally coordinated within a single endocytic event remains unresolved.
  • No integrated structural model of the membrane-bound AP180-clathrin-AP-2-cargo assembly
  • Direct human disease link not established in the corpus
  • Spatiotemporal coordination of phosphorylation, lipid, and ubiquitin regulation unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-5653656 Vesicle-mediated transport 4
Partners
AP2CLTCPLCG1PLD1SNCATUBBVAMP2
Complex memberships
clathrin coat / clathrin-coated vesicle

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 AP180 primary structure was determined: the protein has a three-domain organization with an N-terminal domain (first ~300 residues) harboring a clathrin binding site, an acidic middle domain (~450 residues), and a basic C-terminal domain. Binding of AP180 to clathrin triskelia induces their assembly into 60-70 nm coated structures. cDNA cloning, proteolytic mapping, clathrin assembly in vitro assay The EMBO journal High 8440257
1988 AP180 purified from bovine brain coated vesicles promotes polymerization of clathrin into a homogeneous population of baskets; true molecular weight is ~115 kDa (sedimentation equilibrium) despite anomalous ~180 kDa migration on SDS-PAGE; stoichiometry to clathrin heavy chains in isolated coated vesicles and assembled baskets was determined. Biochemical purification, sedimentation equilibrium, circular dichroism, in vitro clathrin assembly assay Biochemistry High 3191110
1991 AP180 binds directly to clathrin heavy chains independently of clathrin light chains and is incorporated into reassembled clathrin coats in the absence of light chains. In vitro clathrin reassembly, SDS-PAGE, immunoblotting Biochemistry Medium 1909890
1995 AP180 (AP-3) binds inositol hexakisphosphate (InsP6) with Kd ~1.2 µM and 0.9 mol InsP6/mol protein; InsP6 binding inhibits AP180-mediated clathrin cage assembly in vitro but does not affect AP180 binding to preformed cages. Affinity chromatography, peptide sequencing, in vitro binding assay, in vitro clathrin assembly assay The Journal of biological chemistry High 7814377
1999 AP180 and AP-2 interact directly in a clathrin-independent manner; together they assemble clathrin more efficiently at physiological pH than either alone. AP180 is phosphorylated in vivo by casein kinase II (CK2), and phosphorylation weakens AP180-AP2 binding and reduces their cooperative clathrin assembly activity. The AP-2 binding site was localized to AP180 amino acids 623-680. In vitro binding assays, in vitro clathrin assembly, in vitro CK2 phosphorylation, recombinant domain mapping The Journal of biological chemistry High 10428863
1999 The clathrin assembly domain of AP180 (C-terminal domain) is required for synaptic vesicle endocytosis in the squid giant synapse: microinjection of C-terminal AP180 domains enhanced synaptic transmission while a peptide from the C-terminal domain that inhibited clathrin assembly in vitro blocked synaptic transmission, depleted synaptic vesicles, eliminated coated vesicles, and increased plasma membrane perimeter. Microinjection into squid giant presynaptic terminal, electrophysiology, electron microscopy, in vitro clathrin assembly The Journal of neuroscience High 10575017
1999 The C. elegans AP180 ortholog UNC-11 is required for synaptic vesicle biogenesis: unc-11 mutants mislocalize synaptobrevin away from synaptic vesicles and accumulate abnormally large vesicles at synapses, indicating AP180 recruits synaptobrevin to synaptic vesicle membranes and regulates vesicle size during clathrin coat assembly. C. elegans genetics, immunolocalization, electron microscopy Molecular biology of the cell High 10397769
2001 The crystal structure of the ANTH domain of CALM (AP180 homolog) bound to PtdIns(4,5)P2 was determined; a lysine-rich motif mediates PtdIns(4,5)P2 binding. AP180 can simultaneously bind PtdIns(4,5)P2 and clathrin, tethering clathrin to the membrane. In the presence of AP180, clathrin lattices formed on lipid monolayers; when AP-2 was also added, coated pits formed. X-ray crystallography, lipid monolayer budding assay with purified components, in vitro reconstitution Science High 11161218
2001 The C-terminal assembly domains of AP180 and epsin 1 are intrinsically disordered (flexible polypeptide chains with little secondary structure) as shown by hydrodynamic and spectroscopic methods; recombinant AP180 drives in vitro assembly of clathrin cages. Hydrodynamic analysis, circular dichroism, in vitro clathrin assembly The Journal of biological chemistry Medium 11756460
2001 Overexpression of AP180 (or its clathrin-binding domain alone) in cultured cells inhibits clathrin-mediated endocytosis by sequestering cytosolic clathrin, depleting it from the plasma membrane and trans-Golgi network, while AP-1 and AP-2 association with their respective membranes is maintained in the absence of clathrin. Overexpression in cultured cells, transferrin uptake assay, immunofluorescence microscopy Journal of cell science Medium 11148137
2001 AP180 is dephosphorylated (by calcineurin) during depolarization-induced synaptic vesicle endocytosis and rephosphorylated during recovery; unlike dynamin I and synaptojanin, AP180 rephosphorylation is insensitive to PKC antagonists Ro 31-8220 and Go 7874, indicating different kinases phosphorylate different dephosphins. Phosphorylation assays in synaptosomes, pharmacological inhibition of kinases, depolarization protocols Journal of neurochemistry Medium 11145983
2002 In C. elegans, ubiquitination of GLR-1 glutamate receptors promotes their removal from synapses via a pathway requiring UNC-11 (AP180): effects of ubiquitin overexpression on GLR-1 synaptic abundance were blocked by unc-11 mutations, placing AP180 downstream of ubiquitin signaling in regulating glutamate receptor endocytosis. C. elegans genetics (epistasis), GFP reporter imaging, locomotion behavior assay Neuron High 12123612
2002 AP180 is localized predominantly to presynaptic terminals in mammalian neurons, specifically enriched at the cytosolic side of the presynaptic plasma membrane, and is particularly enriched at ribbon synapses in the primate retina where rapid vesicle turnover is required. Immunoelectron microscopy of rat cerebellar neurons and primate retina The Journal of comparative neurology Medium 11977118
2002 AP180 binds to the C-terminal SH2 domain of phospholipase C-gamma1 (PLCγ1) and inhibits PLCγ1 enzymatic activity in a dose-dependent manner; AP180 was found in stable association with PLCγ1 in a clathrin-coated vesicle complex from rat brain. Biochemical purification from rat brain, SH2 domain pulldown, enzyme activity assay Biochemical and biophysical research communications Medium 11779129
2003 The ANTH domain of AP180 interacts directly with tubulin (Kd ~1 µM), and tubulin is co-immunoprecipitated from rat brain extracts with ANTH domain-containing proteins. In vitro binding assay (dissociation constant), co-immunoprecipitation from rat brain The Journal of biological chemistry Medium 12750376
2005 In Drosophila, deletion of the AP180 homolog LAP causes mislocalization of synaptotagmin I, cysteine-string protein, and neuronal synaptobrevin to extrasynaptic axonal regions, along with Dap160, nc82, and glutamate receptors; lap mutations also reduce impulse-evoked transmitter release by disrupting calcium coupling to exocytosis and reducing calcium cooperativity. Drosophila genetics (deletion mutant), electrophysiology, immunocytochemistry, electron microscopy, optical imaging Journal of neurophysiology High 15888532
2007 Membrane anchoring of the AP180 ANTH domain to PtdIns(4,5)P2-containing bilayers is regulated by pH: lowering pH enhances PtdIns(4,5)P2 affinity, and this pH dependency is mediated by conserved histidine residues whose protonation is required for strong PtdIns(4,5)P2 recognition. Liposome binding assay, surface plasmon resonance, NMR, monolayer surface tension, site-directed mutagenesis Journal of molecular biology High 17825837
2008 Knockdown of AP180 in embryonic hippocampal neurons impairs axonal development specifically, whereas overexpression of AP180 causes neurons to generate multiple axons. Endocytosis is reduced in AP180-deficient neurons. AP180 localizes predominantly to a more restricted set of intracellular trafficking organelles compared to CALM. RNA interference knockdown, live imaging, confocal microscopy, transferrin uptake endocytosis assay, ultrastructural analysis in primary neurons The Journal of neuroscience Medium 18842885
2009 In Dictyostelium, AP180 interacts with the cytoplasmic domain of the SNARE protein Vamp7B in vitro; AP180-null mutants show mislocalization and enrichment of Vamp7B on contractile vacuoles and formation of abnormally large contractile vacuoles due to excessive homotypic fusion, indicating AP180 directs Vamp7B into clathrin-coated vesicles to limit homotypic fusion. Gene knockout in Dictyostelium, in vitro binding assay, live imaging, GFP-tagging Molecular biology of the cell Medium 19692567
2009 RNAi-mediated knockdown of AP180 (but not CALM) in a neuronal cell line reduces generation of amyloid-beta peptides Aβ1-40 and Aβ1-42, indicating AP180 specifically regulates amyloid precursor protein (APP) processing pathways. RNAi knockdown in neuronal cell line, ELISA for Aβ peptide levels Biochemical and biophysical research communications Medium 19450545
2011 The ANTH domain of AP180 directly binds the SNARE motif of synaptobrevin 2 (VAMP2), centered around residue M46 in the N-terminal half of the SNARE motif. Depletion of AP180 causes selective surface accumulation of synaptobrevin 2 but not vGLUT1. This establishes AP180 as a cargo-specific endocytic adaptor for synaptobrevin endocytosis. NMR spectroscopy, site-directed mutagenesis, neuronal knockdown with surface protein quantification (selective cargo assay) Proceedings of the National Academy of Sciences of the United States of America High 21808019
2011 The TSP motif (Thr312-Pro314) of human AP180, specifically Ser313, is required for direct binding to the C-terminal region of PLD1 and inhibition of PLD1 enzymatic activity; this inhibitory relationship does not exist between AP180 and PLD2. Transfection/overexpression, deletion mutagenesis, PLD activity assay, binding assay Cancer letters Medium 21296491
2012 RNAi knockdown of AP180 in rat hippocampal neurons results in smaller synaptic puncta and enlargement of synaptic vesicles, as well as reduced density and size of synaptic vesicle clusters at presynaptic terminals. RNAi knockdown in primary hippocampal neurons, fluorescence microscopy with Synaptophysin::EGFP, electron microscopy Neuromolecular medicine Medium 22851330
2014 In Drosophila, acute inactivation of AP180 severely impairs synaptic vesicle recycling at the larval NMJ (reduced FM 1-43 uptake); AP180 activity maintains integrity of synaptic vesicle protein complexes at the plasma membrane during endocytosis; AP180 co-immunoprecipitates with synaptic vesicle proteins including vesicular glutamate transporter and neuronal synaptobrevin. Drosophila genetics, FM 1-43 uptake assay, electron microscopy, co-immunoprecipitation, immunohistochemistry Traffic High 24456281
2015 Loss of AP180 in mice causes activity-dependent reduction of vesicular synaptobrevin 2 (Syb2) levels, defects in synaptic vesicle reformation, and impaired neurotransmission leading to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 in AP180−/−/Syb2+/− mice results in perinatal lethality, establishing that AP180 maintains a large vesicular Syb2 pool necessary for efficient neurotransmission. AP180 knockout mouse, patch-clamp electrophysiology, immunostaining, genetic epistasis (AP180−/−/Syb2+/− double mutant) Neuron High 26412491
2016 A novel conserved sequence in AP180 (LDSSLA[S/N]LVGNLGI) in the ~16 kDa C-terminal subdomain is the major clathrin interaction site; mutation of this sequence causes a deficit in clathrin assembly in vitro. Single or double mutation of DL(L/F) motifs in full-length AP180 had no significant effect on clathrin binding despite higher clathrin affinity for isolated peptides containing these motifs. In vitro clathrin binding assays, clathrin assembly assay, site-directed mutagenesis, transferrin uptake (ex vivo) PloS one Medium 27574975
2019 Multi-site phospho-mimetic mutations (Ser/Thr to Glu) in full-length AP180 reduce clathrin binding and abolish clathrin cage assembly in vitro, supporting a model in which AP180 phosphorylation inhibits clathrin binding and assembly. Site-directed mutagenesis, in vitro clathrin binding assay, in vitro clathrin cage assembly assay Neurochemistry international Medium 31129113
2020 AP180 is required for clathrin-dependent endocytosis and synaptic vesicle reformation in cochlear inner hair cells (IHCs): AP180 knockout mice have severely reduced synaptic vesicle numbers, slowed endocytic membrane retrieval, accumulated endocytic intermediates near ribbon synapses, reduced rate of synaptic vesicle replenishment, high prevalence of multi-tethered/docked SVs after stimulation, and hearing impairment. AP180 was localized predominantly to the synaptic pole of IHCs. AP180 knockout mouse, high-pressure freezing electron tomography, confocal microscopy, patch-clamp membrane capacitance measurements, auditory brainstem response Journal of cell science High 31843760
2021 AP180 is a phosphatidic acid (PA)-binding protein: it binds most strongly to 18:0/22:6-PA (docosahexaenoyl-PA) via its ANTH domain through a lysine-rich motif (K38-K39-K40). 18:0/22:6-PA significantly attenuates AP180's interaction with clathrin, whereas PtdIns(4,5)P2 does not have this effect, revealing a novel mechanism for disassembly of AP180/clathrin cages. Liposome binding assay, domain mapping, site-directed mutagenesis, in vitro clathrin interaction assay Biochemical and biophysical research communications Medium 34864549
2023 α-Synuclein colocalizes with AP180 at clathrin puncta on cell membranes; clathrin puncta containing both α-synuclein and AP180 are significantly larger than those containing either protein alone, indicating functional cooperation in regulating clathrin lattice size at presynaptic membranes. Super-resolution fluorescence microscopy, colocalization analysis, in vitro clathrin assembly on lipid monolayers, immunoelectron microscopy of synaptosomes The Journal of biological chemistry Medium 37516240
2024 NMR spectroscopy identified an extended ~70 residue interaction site within AP180's intrinsically disordered region (IDR) that constitutes the primary, high-affinity binding site for AP2; weaker secondary binding sites contribute at higher AP2 concentrations. The interaction operates in a dynamic equilibrium between bound and unbound states. NMR spectroscopy (atomic-resolution), binding dynamics analysis Nature communications High 39003270
2024 AP180 undergoes calcium-triggered ubiquitination changes in synaptosomes: quantitative mass spectrometry of resting versus stimulated synaptosomes identified significant changes in AP180 ubiquitination in response to calcium influx, among the most pronounced changes detected. Quantitative mass spectrometry of synaptosomes (ubiquitination proteomics), calcium stimulation bioRxivpreprint Low bio_10.1101_2024.07.04.602026
2026 The C-terminal Assembly Domain (AD) of AP180 determines synaptic vesicle size and regulates release properties in C. elegans: an AP180 lacking the AD fails to correct enlarged vesicles; replacing the AD with actin-binding motifs fully restores normal vesicle size and release frequency. Biochemically, the intrinsically disordered AD forms condensates that enrich actin monomers, nucleate filament assembly, and full-length AP180 couples PIP2-rich membranes to actin filaments. C. elegans genetics, in vitro condensate/actin assembly assays, electrophysiology, electron microscopy PLoS biology High 41650190

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science (New York, N.Y.) 626 11161218
2002 Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans. Neuron 236 12123612
1999 UNC-11, a Caenorhabditis elegans AP180 homologue, regulates the size and protein composition of synaptic vesicles. Molecular biology of the cell 232 10397769
2001 Unusual structural organization of the endocytic proteins AP180 and epsin 1. The Journal of biological chemistry 121 11756460
1999 Clathrin functions in the absence of heterotetrameric adaptors and AP180-related proteins in yeast. The EMBO journal 117 10406795
2011 SNARE motif-mediated sorting of synaptobrevin by the endocytic adaptors clathrin assembly lymphoid myeloid leukemia (CALM) and AP180 at synapses. Proceedings of the National Academy of Sciences of the United States of America 114 21808019
1995 Inositol hexakisphosphate binds to clathrin assembly protein 3 (AP-3/AP180) and inhibits clathrin cage assembly in vitro. The Journal of biological chemistry 102 7814377
1993 Clathrin assembly protein AP180: primary structure, domain organization and identification of a clathrin binding site. The EMBO journal 100 8440257
2001 Expression of auxilin or AP180 inhibits endocytosis by mislocalizing clathrin: evidence for formation of nascent pits containing AP1 or AP2 but not clathrin. Journal of cell science 99 11148137
1999 AP180 and AP-2 interact directly in a complex that cooperatively assembles clathrin. The Journal of biological chemistry 93 10428863
1999 A role for the clathrin assembly domain of AP180 in synaptic vesicle endocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 10575017
2015 Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission. Neuron 84 26412491
2001 Protein phosphorylation is required for endocytosis in nerve terminals: potential role for the dephosphins dynamin I and synaptojanin, but not AP180 or amphiphysin. Journal of neurochemistry 79 11145983
2005 AP180 maintains the distribution of synaptic and vesicle proteins in the nerve terminal and indirectly regulates the efficacy of Ca2+-triggered exocytosis. Journal of neurophysiology 69 15888532
2008 Clathrin assembly protein AP180 and CALM differentially control axogenesis and dendrite outgrowth in embryonic hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 58 18842885
1998 Reduced O-glycosylated clathrin assembly protein AP180: implication for synaptic vesicle recycling dysfunction in Alzheimer's disease. Neuroscience letters 49 9756352
1988 Molecular characterization of the AP180 coated vesicle assembly protein. Biochemistry 49 3191110
2005 Synaptic distribution of the endocytic accessory proteins AP180 and CALM. The Journal of comparative neurology 43 15558718
1999 Changes in synaptic expression of clathrin assembly protein AP180 in Alzheimer's disease analysed by immunohistochemistry. Neuroscience 40 10579202
2012 Turning CALM into excitement: AP180 and CALM in endocytosis and disease. Biology of the cell 39 22639918
2013 The Sybtraps: control of synaptobrevin traffic by synaptophysin, α-synuclein and AP-180. Traffic (Copenhagen, Denmark) 35 24279465
2012 Reduction of AP180 and CALM produces defects in synaptic vesicle size and density. Neuromolecular medicine 35 22851330
2007 pH-dependent binding of the Epsin ENTH domain and the AP180 ANTH domain to PI(4,5)P2-containing bilayers. Journal of molecular biology 34 17825837
2014 AP180 couples protein retrieval to clathrin-mediated endocytosis of synaptic vesicles. Traffic (Copenhagen, Denmark) 33 24456281
2002 High-resolution localization of clathrin assembly protein AP180 in the presynaptic terminals of mammalian neurons. The Journal of comparative neurology 31 11977118
2003 A role for epsin N-terminal homology/AP180 N-terminal homology (ENTH/ANTH) domains in tubulin binding. The Journal of biological chemistry 27 12750376
1991 Light-chain-independent binding of adaptors, AP180, and auxilin to clathrin. Biochemistry 24 1909890
2009 AP180-mediated trafficking of Vamp7B limits homotypic fusion of Dictyostelium contractile vacuoles. Molecular biology of the cell 23 19692567
2006 The monomeric clathrin assembly protein, AP180, regulates contractile vacuole size in Dictyostelium discoideum. Molecular biology of the cell 22 17050736
2020 AP180 promotes release site clearance and clathrin-dependent vesicle reformation in mouse cochlear inner hair cells. Journal of cell science 18 31843760
1989 Identification of the clathrin assembly protein AP180 in crude calf brain extracts by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Analytical biochemistry 18 2774183
2014 The Biochemical Properties and Functions of CALM and AP180 in Clathrin Mediated Endocytosis. Membranes 17 25090048
2009 The clathrin assembly protein AP180 regulates the generation of amyloid-beta peptide. Biochemical and biophysical research communications 17 19450545
2010 Clathrin assembly proteins AP180 and CALM in the embryonic rat brain. The Journal of comparative neurology 15 20653035
2007 AP180 and CALM in the developing hippocampus: expression at the nascent synapse and localization to trafficking organelles. The Journal of comparative neurology 15 17640037
2024 An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis. Nature communications 14 39003270
2011 The TSP motif in AP180 inhibits phospholipase D1 activity resulting in increased efficacy of anticancer drug via its direct binding to carboxyl terminal of phospholipase D1. Cancer letters 13 21296491
2011 AP180 and CALM: Dedicated endocytic adaptors for the retrieval of synaptobrevin 2 at synapses. Cellular logistics 11 22279617
2010 Neuronal activity and the expression of clathrin-assembly protein AP180. Biochemical and biophysical research communications 11 20937255
2016 A Novel Sequence in AP180 and CALM Promotes Efficient Clathrin Binding and Assembly. PloS one 10 27574975
2021 Docosahexaenoic acid-containing phosphatidic acid interacts with clathrin coat assembly protein AP180 and regulates its interaction with clathrin. Biochemical and biophysical research communications 9 34864549
2023 α-Synuclein colocalizes with AP180 and affects the size of clathrin lattices. The Journal of biological chemistry 8 37516240
2022 Coarse-Grained Simulations Suggest Potential Competing Roles of Phosphoinositides and Amphipathic Helix Structures in Membrane Curvature Sensing of the AP180 N-Terminal Homology Domain. The journal of physical chemistry. B 7 35394774
2019 AP180 N-Terminal Homology (ANTH) and Epsin N-Terminal Homology (ENTH) Domains: Physiological Functions and Involvement in Disease. Advances in experimental medicine and biology 7 29774507
2003 Immunohistochemical characterization of clathrin assembly protein AP180 and synaptophysin in human brain. Neurobiology of aging 7 12493563
2002 AP180 binds to the C-terminal SH2 domain of phospholipase C-gamma1 and inhibits its enzymatic activity. Biochemical and biophysical research communications 7 11779129
1999 Molecular cloning of clathrin assembly protein gene (rCALM) and its differential expression to AP180 in rat brain. Experimental & molecular medicine 7 10630373
2014 The ∼ 16 kDa C-terminal sequence of clathrin assembly protein AP180 is essential for efficient clathrin binding. PloS one 6 25329427
2012 Synthesis and protein binding studies of a peptide fragment of clathrin assembly protein AP180 bearing an O-linked β-N-acetylglucosaminyl-6-phosphate modification. Organic & biomolecular chemistry 4 22361808
1998 A novel AP180-related protein in vesicles that concentrate at acetylcholine receptor clusters. Journal of cellular biochemistry 4 9493909
2024 The conserved protein adaptors CALM/AP180 and FCHo1/2 cooperatively recruit Eps15 to promote the initiation of clathrin-mediated endocytosis in yeast. PLoS biology 3 39316607
2019 The interaction of assembly protein AP180 and clathrin is inhibited by multi-site phospho-mimetics. Neurochemistry international 2 31129113
2013 Mass spectrometry quantification of PICALM and AP180 in human frontal cortex and neural retina. Analytical biochemistry 2 23954523
2003 Potential role for a novel AP180-related protein during endocytosis in MDCK cells. American journal of physiology. Cell physiology 1 14532018
2026 Endocytic protein AP180 assembly domain regulates synaptic vesicle size and release in Caenorhabditis elegans. PLoS biology 0 41650190
2026 Polarized anionic phospholipids and exocytosis are implicated in the polarized recruitment of budding yeast AP180, an endocytic initiator. Molecular biology of the cell 0 41949887

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