S100A10 (p11, annexin A2 light chain) is a small S100-family EF-hand protein that, uniquely in the family, has lost calcium binding and exists as a constitutive tight homodimer that mimics the Ca2+-activated conformation of other S100 proteins. Each S100A10 dimer binds the N-terminal acetylated peptides of two annexin A2 (ANXA2) molecules to form the (S100A10)2(ANXA2)2 heterotetramer (calpactin I, AIIt), which is anchored at the cytoplasmic face of the plasma membrane and in lipid rafts. Within this complex S100A10 provides hydrophobic binding surfaces that recruit cytoplasmic tails of membrane proteins and other partners. It promotes the trafficking and surface presentation of ion channels and receptors, including the K+ channel TASK-1 (KCNK3), the sodium channel NaV1.8 (SCN10A), the epithelial Ca2+ channels TRPV5/TRPV6, the serotonin 5-HT1B receptor and the chemokine receptor CCR10. It also bridges ANXA2 to the large scaffold AHNAK, linking the complex to cortical actin organization and membrane repair. At the cell surface, S100A10 acts as a plasminogen receptor whose C-terminal lysines bind plasminogen and accelerate t-PA-dependent plasmin generation, contributing to fibrinolysis in vivo. A minor nuclear pool in complex with ANXA2 binds the chromatin remodeler SMARCA3 (HLTF), enhancing its DNA binding and nuclear-matrix retention; in mouse brain this p11-SMARCA3 pathway is required for behavioral and neurogenic responses to antidepressants.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001765 membrane raft assembly | IDA PMID:23861394 Lipid segregation and membrane budding induced by the periph... | MARK AS OVER ANNOTATED | Summary: ANXA2 binding to giant unilamellar vesicles induces clustering of PI(4,5)P2, cholesterol and glycosphingolipids; the ANXA2-S100A10 heterotetramer also does this. Reason: The lipid-segregating activity is a property of ANXA2 (the monomer and even the core domain alone suffice); S100A10 is a passenger in the heterotetramer and does no part of the work in this in vitro GUV system. At most this is a property of the AnxA2-p11 complex, not of S100A10. Supporting Evidence: PMID:23861394 This property is observed for the full-length monomeric protein, a mutant derivative comprising the C-terminal protein core domain and for AnxA2 residing in a heterotetrameric complex with its intracellular binding partner S100A10. |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | REMOVE | Summary: IBA from the S100 family node: calcium ion binding. Reason: S100A10 is the S100 family member that has lost calcium binding: both EF-hand-related sites are degenerate. This is target-specific loss within a clade where the ancestral function is otherwise retained, so the propagation does not apply to S100A10. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN007521306 SUPPORTS SOURCE BUT NOT TARGET S100 family ancestral node; calcium binding via EF-hands is retained in most descendants but both Ca2+-binding loops are degenerate in S100A10, which is Ca2+-insensitive. Supporting Evidence: file:human/S100A10/S100A10-uniprot.txt Does not appear to bind calcium. Contains 2 ancestral PMID:9886297 p11 is a member of the S100 EF-hand protein family, which is unique in having lost its calcium-binding properties |
| GO:0005515 protein binding | IPI PMID:14699089 AHNAK interaction with the annexin 2/S100A10 complex regulat... | MODIFY | Summary: Co-IP/co-fractionation of S100A10 with ANXA2 within the ANXA2/S100A10/AHNAK complex at the plasma membrane of MDCK cells. Reason: S100A10 here acts as the subunit that bridges ANXA2 to the AHNAK C-terminal domain; this is an adaptor activity, which is more informative than protein binding. The ANXA2 interaction per se is captured by GO:1990665 AnxA2-p11 complex. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:14699089 The S100A10 subunit serves to mediate the interaction between annexin 2 and the COOH-terminal regulatory domain of AHNAK. PMID:23275167 Binding of AHNAK to the surface of (p11)(2)(AnxA2)(2) is governed by several hydrophobic interactions between side chains of AHNAK and pockets on S100A10. |
| GO:0005515 protein binding | IPI PMID:14699089 AHNAK interaction with the annexin 2/S100A10 complex regulat... | MODIFY | Summary: S100A10 mediates the interaction of ANXA2 with the C-terminal regulatory domain of AHNAK. Reason: The paper shows S100A10 bridges ANXA2 and AHNAK, supported structurally by the ternary complex structures (PMID:22940583, PMID:23275167). Protein-macromolecule adaptor activity captures this better than protein binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:14699089 The S100A10 subunit serves to mediate the interaction between annexin 2 and the COOH-terminal regulatory domain of AHNAK. PMID:22940583 a single region from the AHNAK C terminus is recruited by an S100A10-annexin A2 heterotetramer, forming an asymmetric ternary complex |
| GO:0005515 protein binding | IPI PMID:23091277 N-terminal acetylation of annexin A2 is required for S100A10... | REMOVE | Summary: In vitro binding of S100A10 to N-terminally acetylated ANXA2 and formation of the heterotetramer. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:23091277 Bacterially expressed and N-terminally acetylated AnxA2 binds S100A10 with an affinity comparable to AnxA2 from porcine tissue and is capable of forming the AnxA2-S100A10 heterotetramer. |
| GO:0005515 protein binding | IPI PMID:23091277 N-terminal acetylation of annexin A2 is required for S100A10... | REMOVE | Summary: Binding of S100A10 to (porcine tissue / acetylated recombinant) annexin A2 measured in vitro. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:23091277 Bacterially expressed and N-terminally acetylated AnxA2 binds S100A10 with an affinity comparable to AnxA2 from porcine tissue and is capable of forming the AnxA2-S100A10 heterotetramer. |
| GO:0005515 protein binding | IPI PMID:23415230 SMARCA3, a chromatin-remodeling factor, is required for p11-... | MODIFY | Summary: AHNAK1 co-immunoprecipitated with WT p11 (dependent on AnxA2 binding) in HEK293 cells; AHNAK peptides bind p11/AnxA2. Reason: The p11/AnxA2 heterotetramer presents a hydrophobic pocket that recruits AHNAK and SMARCA3 peptides; this is an adaptor role for S100A10 rather than generic binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23415230 AHNAK1, SPT6 and SMARCA3 were co-precipitated with WT p11 and the interaction was greatly reduced or abolished by either C83S or C83Q mutation of p11, indicating that the interaction likely needs AnxA2 binding to p11. |
| GO:0005515 protein binding | IPI PMID:23415230 SMARCA3, a chromatin-remodeling factor, is required for p11-... | MODIFY | Summary: SMARCA3 (HLTF) binds a hydrophobic pocket formed by the p11/AnxA2 heterotetramer (crystal structure, pull-downs), which increases SMARCA3 DNA-binding affinity and anchors it in the nuclear matrix. Reason: S100A10, as part of the heterotetramer, recruits SMARCA3 and links it to the nuclear matrix; this is better described as protein-macromolecule adaptor activity than as generic protein binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23415230 SMARCA3, a chromatin-remodeling factor, is a target for the p11/annexin A2 heterotetrameric complex PMID:23415230 p11/AnxA2 not only increases the DNA binding affinity of SMARCA3, but also anchors SMARCA3 to the nuclear matrix presumably via the interaction of AnxA2 with actin and PIP2. |
| GO:0005515 protein binding | IPI PMID:23861394 Lipid segregation and membrane budding induced by the periph... | REMOVE | Summary: Use of the ANXA2-S100A10 heterotetramer in GUV membrane-domain experiments. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:23861394 This property is observed for the full-length monomeric protein, a mutant derivative comprising the C-terminal protein core domain and for AnxA2 residing in a heterotetrameric complex with its intracellular binding partner S100A10. |
| GO:0005515 protein binding | IPI PMID:24457100 Angiogenin interacts with the plasminogen activation system ... | REMOVE | Summary: ANXA2 and S100A10 co-immunoprecipitated with angiogenin in lipid-raft fractions of breast cancer cells. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:24457100 Analysis of lipid raft (LR) and non-lipid raft (NLR) regions of the cell membranes showed the predominance of ANG, A2 and S100-A10 in the LR regions. |
| GO:0005515 protein binding | IPI PMID:26941067 CC chemokine receptor 10 cell surface presentation in melano... | MODIFY | Summary: S100A10 binds directly to the C-terminal cytoplasmic tail of the chemokine receptor CCR10 and regulates its cell-surface presentation. Reason: The partner is a GPCR and binding is direct and functional (surface presentation); G protein-coupled receptor binding is the informative term, consistent with the similar 5-HT1B receptor interaction (PMID:16400147). Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:26941067 S100A10 binds directly to the C-terminal cytoplasmic tail of CCR10 and that this interaction regulates the CCR10 cell surface presentation PMID:16400147 p11 increases localization of 5-HT1B receptors at the cell surface. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: High-throughput crosslinking mass spectrometry of intact nuclei detected an S100A10-ANXA2 crosslink. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:30021884 Here we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein interactions in intact human nuclei. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: High-throughput XL-MS of nuclei detected S100A10-AHNAK crosslinks. Reason: Generic protein binding from a high-throughput screen; the functional AHNAK interaction (adaptor role of S100A10 bridging ANXA2 and AHNAK) is captured by the MODIFY to GO:0030674 on PMID:14699089. Supporting Evidence: PMID:30021884 Here we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein interactions in intact human nuclei. |
| GO:0005515 protein binding | IPI PMID:31837246 High-throughput competitive fluorescence polarization assay ... | MODIFY | Summary: Competitive fluorescence polarization screen of all 20 human S100 proteins against model partner peptides identified TRPM4 peptide binding by S100A10. Reason: TRPM4 is an ion channel; binding to channel cytoplasmic tails is an established, recurrent function of S100A10 (TASK-1, NaV1.8, TRPV5/6), so transmembrane transporter binding is the informative replacement. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:31837246 the complete S100ome (n = 20) was tested against numerous model partners (n = 13) PMID:12198146 We show here that p11 interacts specifically with the TASK-1 K+ channel. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:O75604 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:P33764 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:P60321 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:Q8N5A5-2 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:Q8NB16-2 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary yeast two-hybrid interaction with UniProtKB:Q8WXG8 from the HuRI reference interactome screen. Reason: Generic protein binding from a high-throughput Y2H screen without functional follow-up; uninformative about S100A10 molecular function. Removal does not imply the interaction is false (S100-S100 heterodimers such as with S100A3/S100Z are plausible). Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput AP-MS (BioPlex) detection of S100A10-ANXA2. Reason: Generic protein binding is uninformative about function. The S100A10-ANXA2 interaction itself is well established and is captured more informatively by part_of GO:1990665 AnxA2-p11 complex (and by homodimerization/transporter-binding annotations); removal does not dispute the interaction. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | KEEP AS NON CORE | Summary: Detected by proteomics in extracellular matrix extracts of human varicose veins. Reason: S100A10 is primarily an intracellular protein at the cytoplasmic face of the plasma membrane, but a cell-surface/extracellular pool acting as a plasminogen receptor is documented (PMID:21768297). Detection in tissue extracts is HTP and non-specific, so retain as non-core. Supporting Evidence: PMID:27068509 Extracellular matrix remodelling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. PMID:21768297 S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: active in cytoplasm. Reason: S100A10 is a cytosolic protein that localizes beneath the plasma membrane in complex with ANXA2; cytoplasm is correct though general. Supporting Evidence: PMID:3126079 In tissue culture cells p11-specific antibodies decorated the same submembranous compartment previously seen with antibodies to p36 |
| GO:0005886 plasma membrane | IDA PMID:3126079 The submembranous location of p11 and its interaction with t... | ACCEPT | Summary: NAS (ComplexPortal) plasma membrane location for the AnxA2-p11 complex. Reason: Same paper as the IDA; plasma membrane localization of the complex is well supported. Supporting Evidence: PMID:3126079 In tissue culture cells p11-specific antibodies decorated the same submembranous compartment previously seen with antibodies to p36 |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse S100a10: plasma membrane. Reason: Consistent with experimental data for human/porcine p11 at the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:3126079 In tissue culture cells p11-specific antibodies decorated the same submembranous compartment previously seen with antibodies to p36 |
| GO:0005886 plasma membrane | NAS PMID:3126079 The submembranous location of p11 and its interaction with t... | ACCEPT | Summary: NAS (ComplexPortal) plasma membrane location for the AnxA2-p11 complex. Reason: Same paper as the IDA; plasma membrane localization of the complex is well supported. Supporting Evidence: PMID:3126079 In tissue culture cells p11-specific antibodies decorated the same submembranous compartment previously seen with antibodies to p36 |
| GO:0006900 vesicle budding from membrane | IDA PMID:23861394 Lipid segregation and membrane budding induced by the periph... | MARK AS OVER ANNOTATED | Summary: ANXA2 (monomer or ANXA2-S100A10 heterotetramer) induces inward budding of PI(4,5)P2-rich domains in GUVs. Reason: Membrane budding in this in vitro system is driven by ANXA2 and is specific to it; S100A10 is not required and contributes no demonstrated activity. Annotating S100A10 to vesicle budding over-extends an ANXA2 property. Supporting Evidence: PMID:23861394 This property is observed for the full-length monomeric protein, a mutant derivative comprising the C-terminal protein core domain and for AnxA2 residing in a heterotetrameric complex with its intracellular binding partner S100A10. PMID:23861394 This inward vesiculation is specific for AnxA2 |
| GO:0008289 lipid binding | IDA NOT PMID:23861394 Lipid segregation and membrane budding induced by the periph... | ACCEPT | Summary: NOT lipid binding: S100A10 itself does not bind lipids; membrane binding of the heterotetramer is mediated by ANXA2. Reason: Consistent with the established model in which ANXA2 is the Ca2+-dependent phospholipid-binding subunit and S100A10 is the regulatory light chain; the curator had the full text of PMID:23861394. Note that a later Langmuir-monolayer/solid-state NMR study (PMID:34339205) reported weak interactions of purified S100A10 with unsaturated and anionic phospholipids, so the negation is not absolute in model membranes; physiologically, membrane association of S100A10 is mediated by ANXA2. Supporting Evidence: PMID:23861394 AnxA2 is a cytosolic protein that can bind PI(4,5)P2 and other acidic phospholipids in a Ca(2+)-dependent manner PMID:34339205 However, the membrane binding abilities of S100A10 are not clear. |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse: cell surface. Reason: S100A10 functions as a cell-surface plasminogen receptor on endothelial and other cells (endothelial cells from S100A10-null mice show reduced plasminogen binding). Supporting Evidence: PMID:21768297 endothelial cells from S100A10-null mice demonstrated a 40% reduction in plasminogen binding and plasmin generation in vitro file:human/S100A10/S100A10-deep-research-falcon.md In endothelial cells, macrophages and some cancer cells, S100A10 is displayed on the |
| GO:0010756 positive regulation of plasminogen activation | IDA PMID:9836589 The p11 subunit of the annexin II tetramer plays a key role ... | ACCEPT | Summary: Recombinant p11 stimulates t-PA-dependent Glu-plasminogen activation ~46-fold via its C-terminal lysines, which bind plasminogen; deletion of these lysines abolishes most activity. Reason: Direct biochemical evidence that S100A10 is the plasminogen-binding cofactor of the annexin A2 tetramer, supported in vivo by fibrin accumulation in S100A10-null mice. Supporting Evidence: PMID:9836589 The fluid-phase recombinant p11 subunit stimulated the rate of t-PA-dependent activation of ... plasminogen about 46-fold PMID:9836589 the C-terminal lysine residues of the p11 subunit bind plasminogen and participate in the stimulation of t-PA-dependent activation of plasminogen by AIIt PMID:21768297 S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi |
| GO:0016363 nuclear matrix | NAS PMID:23415230 SMARCA3, a chromatin-remodeling factor, is required for p11-... | KEEP AS NON CORE | Summary: p11 colocalizes with SMARCA3 in the nuclear matrix fraction and is required for SMARCA3 retention there. Reason: Supported by the nuclear matrix fractionation in the paper, but the nuclear pool is minor relative to the plasma-membrane-associated pool. Supporting Evidence: PMID:23415230 In the nuclear matrix, which is prepared after cell permeabilization followed by chromatin digestion, the presence and the colocalization of p11 and SMARCA3 are evident (Figure 4C). |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | MARK AS OVER ANNOTATED | Summary: Detected in ECM-enriched proteomic preparations of normal and diseased tissues. Reason: S100A10 is an intracellular/cell-surface protein; detection in ECM-enriched tissue preparations reflects carryover of cortical/membrane-associated proteins rather than a structural ECM component. Supporting Evidence: PMID:28675934 We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues |
| GO:0042789 mRNA transcription by RNA polymerase II | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer from mouse: mRNA transcription by RNA polymerase II. Reason: S100A10 is not a component of the transcription machinery. The source likely reflects the p11/AnxA2/SMARCA3 regulatory interaction (PMID:23415230), which at most supports regulation of transcription (retained as non-core under GO:0045944), not participation in transcription itself. Supporting Evidence: PMID:23415230 Formation of this complex increases the DNA-binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. |
| GO:0042803 protein homodimerization activity | IDA PMID:23091277 N-terminal acetylation of annexin A2 is required for S100A10... | ACCEPT | Summary: S100A10 forms a tight non-covalent homodimer, the unit that binds two ANXA2 N-termini. Reason: Homodimerization is a defining structural feature of S100 proteins and of S100A10, shown crystallographically. Supporting Evidence: PMID:9886297 The basic unit for p11 is a tight, non-covalent dimer. PMID:9886297 each annexin II peptide forms hydrophobic interactions with both p11 monomers |
| GO:0043547 positive regulation of GTPase activity | IMP PMID:23129259 S100A10 is required for the organization of actin stress fib... | MARK AS OVER ANNOTATED | Summary: S100A10 knockdown suppressed Rac1 activation during cell spreading. Reason: The effect on Rac1 activity is indirect (knockdown phenotype); S100A10 has no GAP/GEF-like activity and no mechanism linking it directly to Rac1 GTPase activity is shown. Supporting Evidence: PMID:23129259 Rac1 activation during spreading was suppressed by S100A10 knockdown, and exogenous expression of active Rac1 restored the ability of cells to spread in the absence of S100A10. |
| GO:0044325 transmembrane transporter binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: transmembrane transporter binding, at an S100A10-specific node. Reason: Binding to cytoplasmic tails of ion channels (TASK-1, NaV1.8, TRPV5/TRPV6) is a well-documented core activity; the target appearing as its own descendant evidence reflects its experimental grounding. Supporting Evidence: PMID:12198146 We show here that p11 interacts specifically with the TASK-1 K+ channel. PMID:12050667 p11 binds directly to the amino terminus of Na(V)1.8 and promotes the translocation of Na(V)1.8 to the plasma membrane, producing functional channels. PMID:12660155 the S100A10-annexin 2 complex plays a crucial role in routing of TRPV5 and TRPV6 to plasma membrane. |
| GO:0044325 transmembrane transporter binding | IPI PMID:12198146 p11, an annexin II subunit, an auxiliary protein associated ... | ACCEPT | Summary: p11 interacts specifically with the C-terminal SSV motif of the TASK-1 K+ channel and is required for its plasma membrane trafficking. Reason: Direct, functionally validated channel binding; one of several channel partners (also NaV1.8, TRPV5/6). Supporting Evidence: PMID:12198146 We show here that p11 interacts specifically with the TASK-1 K+ channel. PMID:12198146 association with p11 is essential for trafficking of TASK-1 to the plasma membrane |
| GO:0045121 membrane raft | IDA PMID:14699089 AHNAK interaction with the annexin 2/S100A10 complex regulat... | ACCEPT | Summary: S100A10 co-fractionates with ANXA2, AHNAK and caveolin-1 in detergent-insoluble lipid raft fractions of MDCK cells. Reason: colocalizes_with membrane raft is appropriately cautious; supported by flotation experiments and independently in breast cancer cells (PMID:24457100). Supporting Evidence: PMID:14699089 In MDCK cells, a significant amount of AHNAK partitioned with annexin 2 and S100A10 into the lipid raft fraction together with caveolin-1 PMID:24457100 Analysis of lipid raft (LR) and non-lipid raft (NLR) regions of the cell membranes showed the predominance of ANG, A2 and S100-A10 in the LR regions. |
| GO:0045921 positive regulation of exocytosis | NAS PMID:22940583 Structure of an asymmetric ternary protein complex provides ... | KEEP AS NON CORE | Summary: ComplexPortal NAS: positive regulation of exocytosis for the AnxA2-p11 complex. Independently supported by work in human endothelial cells showing that S100A10 binds Munc13-4 and the AnxA2-S100A10 complex recruits it to Weibel-Palade body fusion sites. Reason: The cited structure paper (PMID:22940583) concerns AHNAK recruitment and membrane repair rather than exocytosis, but PMID:28450451 directly supports a role: S100A10 is a Munc13-4 interactor and AnxA2-S100A10 helps tether Weibel-Palade bodies to the plasma membrane for stimulated exocytosis. Retained as a genuine but non-core (cell-type-specific) role. Supporting Evidence: PMID:28450451 We also identify the S100A10 subunit of the annexin A2 (AnxA2)-S100A10 protein complex as a novel Munc13-4 interactor and show that AnxA2-S100A10 participates in recruiting Munc13-4 to WPB fusion sites. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse: positive regulation of transcription by RNA polymerase II. Reason: The p11/AnxA2 complex increases SMARCA3 DNA-binding affinity and SMARCA3-dependent reporter transcription; a regulatory but peripheral role relative to the membrane functions. Supporting Evidence: PMID:23415230 Formation of this complex increases the DNA-binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. |
| GO:0048306 calcium-dependent protein binding | IBA GO_REF:0000033 | REMOVE | Summary: IBA: calcium-dependent protein binding. Reason: S100A10 has lost calcium binding and binds its targets (ANXA2, channels) in a Ca2+-independent manner, unlike other S100 proteins; the family-level calcium-dependent target binding does not apply. Its partner binding is captured by complex membership and transporter-binding terms. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN007521306 SUPPORTS SOURCE BUT NOT TARGET S100 family ancestral node; calcium binding via EF-hands is retained in most descendants but both Ca2+-binding loops are degenerate in S100A10, which is Ca2+-insensitive. Supporting Evidence: file:human/S100A10/S100A10-uniprot.txt Does not appear to bind calcium. Contains 2 ancestral PMID:9836589 plasminogen by the p11 subunit was Ca2+-independent |
| GO:0050767 regulation of neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse: regulation of neurogenesis. Reason: In mouse, SSRI-induced hippocampal neurogenesis depends on the p11/AnxA2/SMARCA3 pathway; this is a downstream, context-specific role. Supporting Evidence: PMID:23415230 Our data indicate that the p11/AnxA2/SMARCA3 pathway mediates both neurogenic and behavioral responses to SSRIs. |
| GO:0051496 positive regulation of stress fiber assembly | IMP PMID:23129259 S100A10 is required for the organization of actin stress fib... | KEEP AS NON CORE | Summary: S100A10 depletion disrupted stress fiber formation. Reason: Knockdown phenotype, likely indirect via Rac1 and cortical actin organization by the AnxA2-p11 complex; peripheral to core function. Supporting Evidence: PMID:23129259 Depletion of S100A10 induced disruption of stress fiber formation and delay in cell spreading. |
| GO:0051894 positive regulation of focal adhesion assembly | IMP PMID:23129259 S100A10 is required for the organization of actin stress fib... | KEEP AS NON CORE | Summary: S100A10 knockdown affected focal adhesion/actin organization during spreading. Reason: Indirect knockdown phenotype in a single study; retained as non-core. Supporting Evidence: PMID:23129259 Depletion of S100A10 induced disruption of stress fiber formation and delay in cell spreading. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Identified in the proteome of human urinary exosomes. Reason: HTP proteomic detection; S100A10/ANXA2 are common exosome cargo, but this is not a site of function. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0072659 protein localization to plasma membrane | IDA PMID:12198146 p11, an annexin II subunit, an auxiliary protein associated ... | ACCEPT | Summary: Association with p11 masks an ER-retention signal of TASK-1 and is essential for its trafficking to the plasma membrane. Reason: Core process: S100A10 promotes surface delivery of multiple membrane proteins (TASK-1, NaV1.8, TRPV5/6, 5-HT1B, CCR10). Supporting Evidence: PMID:12198146 association with p11 is essential for trafficking of TASK-1 to the plasma membrane PMID:12050667 p11 binds directly to the amino terminus of Na(V)1.8 and promotes the translocation of Na(V)1.8 to the plasma membrane, producing functional channels. PMID:12660155 the S100A10-annexin 2 complex plays a crucial role in routing of TRPV5 and TRPV6 to plasma membrane. PMID:16400147 p11 increases localization of 5-HT1B receptors at the cell surface. |
| GO:0090575 RNA polymerase II transcription regulator complex | EXP PMID:23415230 SMARCA3, a chromatin-remodeling factor, is required for p11-... | KEEP AS NON CORE | Summary: ComplexPortal: the p11/AnxA2/SMARCA3 ternary complex as an RNA polymerase II transcription regulator complex. Reason: Supported by co-IP, crystal structure and nuclear matrix data for the ternary complex, which regulates SMARCA3 transcriptional activity; peripheral to the main membrane-associated roles. Supporting Evidence: PMID:23415230 SMARCA3, a chromatin-remodeling factor, is a target for the p11/annexin A2 heterotetrameric complex PMID:23415230 Formation of this complex increases the DNA-binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. |
| GO:0090575 RNA polymerase II transcription regulator complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse of the same complex membership. Reason: As for the EXP annotation, non-core. Supporting Evidence: PMID:23415230 SMARCA3, a chromatin-remodeling factor, is a target for the p11/annexin A2 heterotetrameric complex |
| GO:0098797 plasma membrane protein complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer: plasma membrane protein complex. Reason: The AnxA2-p11 heterotetramer (and its AHNAK ternary complex) is a plasma-membrane-associated protein complex. Supporting Evidence: PMID:23091277 only the complex is firmly anchored in the plasma membrane, where it functions in the plasma membrane targeting/recruitment of certain ion channels and receptors |
| GO:0098797 plasma membrane protein complex | IPI PMID:23275167 Structure of a C-terminal AHNAK peptide in a 1:2:2 complex w... | ACCEPT | Summary: Crystal structure of the AHNAK C-terminal peptide bound to the S100A10-AnxA2 heterotetramer, a complex that co-localizes at the intracellular face of the plasma membrane. Reason: Structural evidence for the membrane-associated AHNAK-AnxA2-S100A10 complex. Supporting Evidence: PMID:23275167 Binding of AHNAK to the surface of (p11)(2)(AnxA2)(2) is governed by several hydrophobic interactions between side chains of AHNAK and pockets on S100A10. PMID:23275167 All three proteins co-localize at the intracellular face of the plasma membrane in a Ca(2+)-dependent manner. |
| GO:0098797 plasma membrane protein complex | IPI PMID:9886297 The crystal structure of a complex of p11 with the annexin I... | ACCEPT | Summary: Crystal structure of p11 with the annexin II N-terminal peptide. Reason: Defines the AnxA2-p11 heterotetramer, which is a plasma-membrane-associated complex. Supporting Evidence: PMID:9886297 each annexin II peptide forms hydrophobic interactions with both p11 monomers |
| GO:1900026 positive regulation of substrate adhesion-dependent cell spreading | IMP PMID:23129259 S100A10 is required for the organization of actin stress fib... | KEEP AS NON CORE | Summary: S100A10 depletion delayed cell spreading; rescued by active Rac1. Reason: Knockdown phenotype in cultured cells, indirect; non-core. Supporting Evidence: PMID:23129259 Depletion of S100A10 induced disruption of stress fiber formation and delay in cell spreading. PMID:23129259 Rac1 activation during spreading was suppressed by S100A10 knockdown, and exogenous expression of active Rac1 restored the ability of cells to spread in the absence of S100A10. |
| GO:1905686 positive regulation of plasma membrane repair | NAS PMID:22940583 Structure of an asymmetric ternary protein complex provides ... | KEEP AS NON CORE | Summary: The S100A10-AnxA2 heterotetramer recruits AHNAK, a dysferlin partner in muscle membrane repair. Reason: The structural work supports a model in which the complex targets AHNAK to the membrane during repair; plausible role but not directly demonstrated for S100A10 in a repair assay. Supporting Evidence: PMID:22940583 which along with dysferlin, functions in muscle and cardiac tissue repair PMID:22940583 a single region from the AHNAK C terminus is recruited by an S100A10-annexin A2 heterotetramer, forming an asymmetric ternary complex |
| GO:1990665 AnxA2-p11 complex | IDA PMID:23091277 N-terminal acetylation of annexin A2 is required for S100A10... | ACCEPT | Summary: S100A10 forms the AnxA2-S100A10 heterotetramer with N-terminally acetylated AnxA2. Reason: Defining complex membership of S100A10 (annexin A2 light chain). Supporting Evidence: PMID:23091277 Bacterially expressed and N-terminally acetylated AnxA2 binds S100A10 with an affinity comparable to AnxA2 from porcine tissue and is capable of forming the AnxA2-S100A10 heterotetramer. PMID:9886297 each annexin II peptide forms hydrophobic interactions with both p11 monomers |
| GO:1990665 AnxA2-p11 complex | IDA PMID:23861394 Lipid segregation and membrane budding induced by the periph... | ACCEPT | Summary: AnxA2 residing in a heterotetrameric complex with S100A10 was used in GUV experiments. Reason: Complex membership is well established. Supporting Evidence: PMID:23861394 This property is observed for the full-length monomeric protein, a mutant derivative comprising the C-terminal protein core domain and for AnxA2 residing in a heterotetrameric complex with its intracellular binding partner S100A10. |
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Download this section (compressed HTML)Q: How does S100A10 reach the outer leaflet/cell surface to act as a plasminogen receptor, given that it lacks a signal peptide and its partner ANXA2 is also cytosolic?
Q: Is a molecular-function term for plasminogen binding (cofactor of t-PA-mediated plasminogen activation) warranted for S100A10, analogous to other cell-surface plasminogen receptors?
Q: Does S100A10 promote surface delivery of channels and receptors only as part of the AnxA2-p11 heterotetramer, or can free S100A10 dimers (stabilized against degradation) act independently?
Q: Is the AnxA2-p11-dependent regulation of SMARCA3 relevant outside the hippocampal antidepressant context, e.g. in PAI-1 transcription in endothelial cells?
Experiment: Compare surface biotinylation of TASK-1, NaV1.8 and TRPV5 in S100a10-null versus Anxa2-null primary cells, rescuing with S100A10 mutants that cannot bind ANXA2 (e.g. C83 or hydrophobic-pocket mutants).
Hypothesis: S100A10 is required for surface delivery of its channel partners in vivo independent of ANXA2.
Type: genetic and cell biology
Experiment: Knock-in mice expressing S100A10 lacking the C-terminal lysines, assessed for vascular fibrin deposition, thrombus clearance and endothelial plasmin generation.
Hypothesis: The C-terminal lysines of S100A10 are necessary for fibrinolysis in vivo.
Type: in vivo genetics
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