ATCAY (caytaxin, BNIP-H) is a neuron-restricted member of the BNIP-2 family. It has an N-terminal region carrying a kinesin light chain-binding ELEWED motif and a C-terminal CRAL-TRIO/BCH domain. It acts as a kinesin-1 cargo adaptor, moving along axons and dendrites to neurite terminals and growth cones. There it delivers metabolic enzymes for transmitter synthesis: it binds kidney-type glutaminase, relocating it from mitochondria and lowering glutamate production, and it links ATP citrate lyase to KLC1 and recruits choline acetyltransferase for local acetylcholine synthesis that promotes neurite outgrowth. It may also help position mitochondria in neurites. Caytaxin is ubiquitinated by CHIP, binds PIN1 after NGF stimulation, and is cleaved by caspase-3 at presynapses. Loss-of-function mutations cause recessive Cayman ataxia in humans and ataxia or dystonia in jittery, sidewinder and hesitant mice and the dystonic rat.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:16275660 Identification of VCP/p97, carboxyl terminus of Hsp70-intera... | MODIFY | Summary: Protein binding (IPI) with the E3 ligase CHIP (STUB1), from a protein-array screen confirmed by pull-down and co-IP. CHIP polyubiquitinates caytaxin, and a later study mapped the ubiquitinated lysines. Caytaxin is the ligase's substrate, so ubiquitin protein ligase binding is the informative term. Reason: [PMID:16275660 "CHIP e.g. was found to efficiently polyubiquitinate caytaxin in vitro, suggesting that it might influence caytaxin degradation in vivo."] [PMID:39703232 "Additionally, CHIP-mediated ubiquitination of BNIP-H is completely inhibited when BNIP-H bears arginine mutations at four key lysine residues."] Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16275660 CHIP e.g. was found to efficiently polyubiquitinate caytaxin in vitro, suggesting that it might influence caytaxin degradation in vivo. PMID:39703232 Additionally, CHIP-mediated ubiquitination of BNIP-H is completely inhibited when BNIP-H bears arginine mutations at four key lysine residues. |
| GO:0005515 protein binding | IPI PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | MODIFY | Summary: Protein binding (IPI) with mouse kidney-type glutaminase (KGA). Caytaxin and KGA form an endogenous complex in brain and bind directly. Caytaxin relocates KGA from mitochondria to neurite terminals and lowers glutamate by inhibiting KGA activity. Enzyme binding is the informative term; the cached abstract reports inhibition in cells and does not say whether it is direct. Reason: [PMID:16899818 "Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:16899818 "It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity."] Proposed replacements: enzyme binding Supporting Evidence: PMID:16899818 Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:16899818 It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. |
| GO:0005515 protein binding | IPI PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | MODIFY | Summary: Protein binding (IPI) with human glutaminase (GLS). Caytaxin and KGA form an endogenous complex in brain and bind directly. Caytaxin relocates KGA from mitochondria to neurite terminals and lowers glutamate by inhibiting KGA activity. Enzyme binding is the informative term; the cached abstract reports inhibition in cells and does not say whether it is direct. Reason: [PMID:16899818 "Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:16899818 "It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity."] Proposed replacements: enzyme binding Supporting Evidence: PMID:16899818 Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:16899818 It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. |
| GO:0005515 protein binding | IPI PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | MODIFY | Summary: Protein binding (IPI) with rat kidney-type glutaminase (KGA). Caytaxin and KGA form an endogenous complex in brain and bind directly. Caytaxin relocates KGA from mitochondria to neurite terminals and lowers glutamate by inhibiting KGA activity. Enzyme binding is the informative term; the cached abstract reports inhibition in cells and does not say whether it is direct. Reason: [PMID:16899818 "Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:16899818 "It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity."] Proposed replacements: enzyme binding Supporting Evidence: PMID:16899818 Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:16899818 It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. |
| GO:0005515 protein binding | IPI PMID:18628984 Nerve growth factor stimulates interaction of Cayman ataxia ... | MODIFY | Summary: Protein binding (IPI) with rat kidney-type glutaminase (KGA), from the caytaxin-PIN1 study, which co-immunoprecipitates endogenous KGA with caytaxin and shows that PIN1 competes it off under NGF stimulation. Caytaxin binds KGA, relocalizes it to neurites and inhibits its activity. Enzyme binding is the informative term. Reason: [PMID:18628984 "Furthermore, Pin1 disrupted the BNIP-H/glutaminase-binding in PC12 cells under nerve growth factor-stimulation."] [PMID:18628984 "In the case of glutaminase, we have shown that BNIP-H is able to inhibit its enzyme activity as well as to relocalize glutaminase from mitochondria in the cell body to neurites [6]."] Proposed replacements: enzyme binding Supporting Evidence: PMID:18628984 Furthermore, Pin1 disrupted the BNIP-H/glutaminase-binding in PC12 cells under nerve growth factor-stimulation. PMID:18628984 In the case of glutaminase, we have shown that BNIP-H is able to inhibit its enzyme activity as well as to relocalize glutaminase from mitochondria in the cell body to neurites [6]. |
| GO:0005515 protein binding | IPI PMID:18628984 Nerve growth factor stimulates interaction of Cayman ataxia ... | MODIFY | Summary: Protein binding (IPI) with the peptidyl-prolyl isomerase PIN1. The interaction is characterized in detail: it is enhanced by NGF, maps to two atypical WW-domain-binding sites in the caytaxin C-terminus, and competes with glutaminase binding. As with the glutaminase and CHIP rows, the partner is an enzyme, so enzyme binding is the informative replacement. Whether PIN1 isomerizes caytaxin is not established. Reason: [PMID:18628984 "We have characterized the interaction between BNIP-H and Pin1 in differentiating neurons and have further shown that NGF-stimulation of PC12 cells strongly enhanced their interaction via distinct binding motifs"] [PMID:18628984 "Furthermore, Pin1 disrupted the BNIP-H/glutaminase-binding in PC12 cells under nerve growth factor-stimulation."] Proposed replacements: enzyme binding Supporting Evidence: PMID:18628984 We have characterized the interaction between BNIP-H and Pin1 in differentiating neurons and have further shown that NGF-stimulation of PC12 cells strongly enhanced their interaction via distinct binding motifs PMID:18628984 Furthermore, Pin1 disrupted the BNIP-H/glutaminase-binding in PC12 cells under nerve growth factor-stimulation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Protein binding (IPI) with KLC1, from the HuRI yeast two-hybrid map. This independently confirms the kinesin light chain interaction mapped to caytaxin's ELEWED motif. Kinesin binding is the informative term. Reason: [PMID:19861499 "Our yeast two-hybrid screen identified kinesin light chains (KLCs) as caytaxin-binding proteins."] [PMID:19861499 "The tetratricopeptide-repeat region of KLC1 recognizes the ELEWED sequence (amino acids 115-120) of caytaxin."] Proposed replacements: kinesin binding Supporting Evidence: PMID:19861499 Our yeast two-hybrid screen identified kinesin light chains (KLCs) as caytaxin-binding proteins. PMID:19861499 The tetratricopeptide-repeat region of KLC1 recognizes the ELEWED sequence (amino acids 115-120) of caytaxin. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm (IBA). Caytaxin is a soluble cytoplasmic protein distributed along neurites. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001087311 SUPPORTS TRANSFER BCH-domain family node with yeast, fly and human members, including ATCAY itself (Q86WG3). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0005737 cytoplasm | IDA PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | ACCEPT | Summary: Cytoplasm (IDA). Caytaxin is a soluble cytoplasmic protein distributed along neurites. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm (IEA, UniProt subcellular location). Caytaxin is a soluble cytoplasmic protein distributed along neurites. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0005739 mitochondrion | IDA NOT PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | ACCEPT | Summary: NOT colocalizes with mitochondrion (IDA). This is the curator's reading of the PC12 data in PMID:16899818, whose full text is not cached. The abstract states only that caytaxin relocates KGA from mitochondria to neurite terminals, which implies that caytaxin's own pool is extramitochondrial in that system. In hippocampal neurons, by contrast, part of the caytaxin pool colocalizes with mitochondria. The two results differ in cell type and probably in the pool scored, and a partial, motor-associated contact is compatible with caytaxin not being a mitochondrial protein. Accepted, deferring to the curator. Reason: [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:19861499 "A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites."] Supporting Evidence: PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:19861499 A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Mitochondrion (ISS, from rat caytaxin). Only part of the caytaxin pool colocalizes with mitochondria in neurites, consistent with a kinesin adaptor that may carry mitochondria. Caytaxin has no mitochondrial targeting signal, and the human IDA data record it as NOT colocalizing with mitochondria. 'Located in mitochondrion' overstates a partial, likely cargo-associated contact. Reason: [PMID:19861499 "A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q1M168 SOURCE WEAK OR INFERRED Rat caytaxin: only partial colocalization with mitochondria in neurites (PMID:19861499); 'located in' overstates a likely cargo-associated contact. Supporting Evidence: PMID:19861499 A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Apoptotic process (IBA). The donor is BNIPL, a pro-apoptotic BNIP-2-family paralog. Caytaxin's characterized roles are neuronal: a kinesin cargo adaptor that targets KGA and ATP citrate lyase to neurite terminals. It is a caspase-3 substrate at the presynapse, but being cleaved by caspases is not participation in apoptosis, and no apoptotic function of caytaxin is reported. Over-annotation for this neuron-specific paralog. Reason: [PMID:21369758 "Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse."] [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- FUNCTION: Functions in the development of neural tissues, particularly"] Propagation Review Root cause: PROPAGATION BAD Sources checked: PANTHER:PTN000251507 SUPPORTS SOURCE BUT NOT TARGET Node whose apoptosis evidence comes from BNIPL (Q7Z465). ATCAY has diverged into a neuron-restricted transport adaptor with no reported apoptotic role, so the function looks lineage-specific to BNIPL rather than ancestral. Supporting Evidence: PMID:21369758 Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse. PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. file:human/ATCAY/ATCAY-uniprot.txt CC -!- FUNCTION: Functions in the development of neural tissues, particularly |
| GO:0019894 kinesin binding | IPI PMID:19861499 Cayman ataxia protein caytaxin is transported by kinesin alo... | ACCEPT | Summary: Kinesin binding (IPI). The KLC1 TPR domain binds caytaxin's ELEWED motif (residues 115-120), a motif shared with other kinesin cargo adaptors. Caytaxin moves along neurites at kinesin speeds and links KLC1 to ATP citrate lyase for transport to neurite terminals. Core function. Reason: [PMID:19861499 "Our yeast two-hybrid screen identified kinesin light chains (KLCs) as caytaxin-binding proteins."] [PMID:19861499 "The tetratricopeptide-repeat region of KLC1 recognizes the ELEWED sequence (amino acids 115-120) of caytaxin."] [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] Supporting Evidence: PMID:19861499 Our yeast two-hybrid screen identified kinesin light chains (KLCs) as caytaxin-binding proteins. PMID:19861499 The tetratricopeptide-repeat region of KLC1 recognizes the ELEWED sequence (amino acids 115-120) of caytaxin. PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. |
| GO:0030424 axon | IEA GO_REF:0000120 | ACCEPT | Summary: Axon (IEA, rat ortholog projection). Caytaxin is distributed in punctate patterns in both axons and dendrites of hippocampal neurons, moving with kinesin-1. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell projection, axon"] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, axon |
| GO:0030424 axon | ISS GO_REF:0000024 | ACCEPT | Summary: Axon (ISS, from rat caytaxin). Caytaxin is distributed in punctate patterns in both axons and dendrites of hippocampal neurons, moving with kinesin-1. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell projection, axon"] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, axon |
| GO:0030425 dendrite | IEA GO_REF:0000120 | ACCEPT | Summary: Dendrite (IEA, rat ortholog projection). Caytaxin is distributed in punctate patterns in both axons and dendrites of hippocampal neurons, moving with kinesin-1. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell projection, axon"] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, axon |
| GO:0030425 dendrite | ISS GO_REF:0000024 | ACCEPT | Summary: Dendrite (ISS, from rat caytaxin). Caytaxin is distributed in punctate patterns in both axons and dendrites of hippocampal neurons, moving with kinesin-1. Accepted. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell projection, axon"] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, axon |
| GO:0030426 growth cone | IEA GO_REF:0000044 | ACCEPT | Summary: Growth cone (IEA, UniProt subcellular location). Caytaxin accumulates in growth cones, and this depends on kinesin-1. Accepted. Reason: [PMID:19861499 "Inhibition of kinesin-1 by dominant-negative KHC decreases the accumulation of caytaxin in the growth cone."] Supporting Evidence: PMID:19861499 Inhibition of kinesin-1 by dominant-negative KHC decreases the accumulation of caytaxin in the growth cone. |
| GO:0031175 neuron projection development | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Neuron projection development (IEA, mouse/rat ortholog projection). Caytaxin promotes neurite outgrowth by bringing ATP citrate lyase, and then choline acetyltransferase, to neurite terminals for local acetylcholine production. A disease mutant fails to do so. This is a downstream outcome of its transport-adaptor role, so it is kept as non-core. Reason: [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [PMID:26343454 "In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). UniProtKB:Q8BHE3 SUPPORTS TRANSFER Mouse caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. PMID:26343454 In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth. |
| GO:0031175 neuron projection development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuron projection development (ISS, from mouse caytaxin). Caytaxin promotes neurite outgrowth by bringing ATP citrate lyase, and then choline acetyltransferase, to neurite terminals for local acetylcholine production. A disease mutant fails to do so. This is a downstream outcome of its transport-adaptor role, so it is kept as non-core. Reason: [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [PMID:26343454 "In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8BHE3 SUPPORTS TRANSFER Mouse caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. PMID:26343454 In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth. |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Mitochondrial membrane (ISS, from mouse caytaxin). Same basis as the mitochondrion row: partial colocalization of a cytosolic kinesin adaptor with mitochondria. The cited sources give no evidence that caytaxin is a mitochondrial membrane protein, and human IDA data place it outside mitochondria. Over-annotation. Reason: [PMID:19861499 "A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q8BHE3 UNRESOLVED Mouse caytaxin: the basis for a mitochondrial membrane location could not be traced; no cited study places caytaxin in a mitochondrial membrane. Supporting Evidence: PMID:19861499 A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0043005 neuron projection | IDA PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | ACCEPT | Summary: Neuron projection (IDA). Caytaxin localizes along neurites and concentrates, with its cargoes KGA and ATP citrate lyase, at neurite terminals. Accepted. Reason: [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] Supporting Evidence: PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | ACCEPT | Summary: Neuron projection (IEA, mouse ortholog projection). Caytaxin localizes along neurites and concentrates, with its cargoes KGA and ATP citrate lyase, at neurite terminals. Accepted. Reason: [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BHE3 SUPPORTS TRANSFER Mouse caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. |
| GO:0044306 neuron projection terminus | IEA GO_REF:0000107 | ACCEPT | Summary: Neuron projection terminus (IEA, rat ortholog projection). Caytaxin localizes along neurites and concentrates, with its cargoes KGA and ATP citrate lyase, at neurite terminals. Accepted. Reason: [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] [PMID:26343454 "Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals."] [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. PMID:26343454 Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. |
| GO:0045202 synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Synapse (IEA, rat ortholog projection). Caytaxin is a presynaptic protein, cleaved by caspase-3 at the presynapse, and it delivers KGA and ATP citrate lyase to neurite terminals for transmitter synthesis. Accepted. Reason: [PMID:21369758 "Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:21369758 Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0045202 synapse | ISS GO_REF:0000024 | ACCEPT | Summary: Synapse (ISS, from rat caytaxin). Caytaxin is a presynaptic protein, cleaved by caspase-3 at the presynapse, and it delivers KGA and ATP citrate lyase to neurite terminals for transmitter synthesis. Accepted. Reason: [PMID:21369758 "Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:21369758 Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0048311 mitochondrion distribution | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrion distribution (IEA, rat ortholog projection). RNAi knockdown of caytaxin shifts mitochondria away from distal neurites, and UniProt proposes that it links mitochondria to KLC1. This is plausible for a kinesin adaptor, but it rests on one knockdown observation, and the cited abstract does not show direct binding to mitochondria. Kept as non-core. Reason: [PMID:19861499 "A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBUNIT: Interacts with KLC1; may link mitochondria to KLC1 and"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBUNIT: Interacts with KLC1; may link mitochondria to KLC1 and |
| GO:0048311 mitochondrion distribution | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrion distribution (ISS, from rat caytaxin). RNAi knockdown of caytaxin shifts mitochondria away from distal neurites, and UniProt proposes that it links mitochondria to KLC1. This is plausible for a kinesin adaptor, but it rests on one knockdown observation, and the cited abstract does not show direct binding to mitochondria. Kept as non-core. Reason: [PMID:19861499 "A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites."] [file:human/ATCAY/ATCAY-uniprot.txt "CC -!- SUBUNIT: Interacts with KLC1; may link mitochondria to KLC1 and"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 A part of caytaxin, however, colocalizes with mitochondria and suppression of caytaxin expression by RNAi redistributes mitochondria away from the distal ends of neurites. file:human/ATCAY/ATCAY-uniprot.txt CC -!- SUBUNIT: Interacts with KLC1; may link mitochondria to KLC1 and |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear region of cytoplasm (IEA, rat ortholog projection). Plausible for a soluble cytosolic protein, but its functionally relevant pools are along neurites and at their terminals. Kept as non-core. Reason: [PMID:19861499 "In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q1M168 SUPPORTS TRANSFER Rat caytaxin; the neuronal localization and roles are shared with human caytaxin, which rescues ataxic Atcay mutant mice (PMID:23226316). Supporting Evidence: PMID:19861499 In cultured hippocampal neurons, we found that caytaxin is distributed in both axons and dendrites in punctate patterns, and it colocalizes with microtubules and KHC. |
| GO:0062133 negative regulation of L-glutamine biosynthetic process | IDA PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | MODIFY | Summary: Negative regulation of L-glutamine biosynthetic process (IDA). The finding is that caytaxin inhibits kidney-type glutaminase, which converts glutamine to glutamate, and so lowers glutamate. That is negative regulation of glutamate production, not of glutamine synthesis, which is catalysed by glutamine synthetase. The term direction appears inverted; negative regulation of L-glutamate biosynthetic process states the result. Reason: [PMID:16899818 "KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter."] [PMID:16899818 "It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity."] Proposed replacements: negative regulation of L-glutamate biosynthetic process Supporting Evidence: PMID:16899818 KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter. PMID:16899818 It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. |
| GO:0098793 presynapse | EXP PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ... | ACCEPT | Summary: Presynapse (EXP). Caytaxin is a presynaptic protein, cleaved by caspase-3 at the presynapse, and it delivers KGA and ATP citrate lyase to neurite terminals for transmitter synthesis. Accepted. Reason: [PMID:21369758 "Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Supporting Evidence: PMID:21369758 Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
| GO:0098793 presynapse | IEA GO_REF:0000044 | ACCEPT | Summary: Presynapse (IEA, UniProt subcellular location). Caytaxin is a presynaptic protein, cleaved by caspase-3 at the presynapse, and it delivers KGA and ATP citrate lyase to neurite terminals for transmitter synthesis. Accepted. Reason: [PMID:21369758 "Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse."] [PMID:16899818 "Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals."] Supporting Evidence: PMID:21369758 Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse. PMID:16899818 Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. |
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Download this section (compressed HTML)Q: Is the Cayman ataxia phenotype mainly due to loss of glutaminase targeting, of cholinergic machinery targeting, or of mitochondrial positioning at cerebellar synapses?
Q: Does caytaxin inhibit purified kidney-type glutaminase directly, which would warrant enzyme inhibitor activity (GO:0004857), or only by moving it away from mitochondria?
Experiment: Screen recombinant caytaxin CRAL-TRIO domain against lipid and lipophilic metabolite libraries, and test ELEWED-motif mutants for rescue of cargo delivery and motor phenotypes in Atcay-null mice.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: What, if any, lipophilic ligand caytaxin's CRAL-TRIO domain binds, and whether ligand binding regulates its cargo adaptor function, is unknown.
OPEN BIOLOGY
What is known: Established: neuron-restricted kinesin-1 adaptor that binds KLC1, KGA and ATP citrate lyase, and loss causes ataxia. Predicted: a CRAL-TRIO small-molecule-binding domain with a ligand more polar than vitamin E (modelling). Not established: any bound ligand or its role.
Provenance (the field's own admissions):
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