AKAIN1 (A-kinase anchor protein inhibitor 1, formerly C18orf42) is a 69-residue protein expressed preferentially in neural tissue that binds the type II regulatory subunits of cAMP-dependent protein kinase A, RIIalpha (PRKAR2A) and RIIbeta (PRKAR2B). Its RII-binding site is predicted to form an amphipathic helix, the same structural element A-kinase anchoring proteins (AKAPs) use to dock onto the dimerization/docking domain of the RII dimer. Unlike an AKAP, however, AKAIN1 has no targeting domain to carry PKA anywhere: occupying the docking surface instead competes with AKAPs, and expression of AKAIN1 blocks AKAP-mediated subcellular localization of PKA. It has therefore been proposed to act as an endogenous disruptor of PKA-AKAP interactions, a naturally occurring counterpart to the synthetic anchoring-disruptor peptides used experimentally. Endogenous AKAIN1 protein is translated and associates with PKA subunits, but whether it displaces PKA from AKAPs at physiological levels, and what that does in neurons, has not been established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding with ROPN1 (ropporin-1A), from the HuRI binary interactome screen. Removed as uninformative; the interaction itself is interesting and is raised as a question. Reason: This row records that AKAIN1 scored an interaction with ROPN1 (Q9HAT0) in HuRI [PMID:32296183 "Here we present a human 'all-by-all'"], a proteome-scale screen rather than a study of AKAIN1. Per the project's GO:0005515 policy the term is removed as uninformative - this is not a claim that the interaction is false, and HuRI does not characterise it well enough to support a more specific molecular function. It is worth flagging, though, because it may not be incidental: ROPN1 carries a ropporin dimerization/docking domain (InterPro IPR047844), and ropporins are AKAP-associated proteins. An amphipathic-helix PKA-RII binder hitting a docking-domain protein is the shape of interaction AKAIN1 is known for. Recorded under suggested_questions rather than asserted. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytosol, by Ensembl Compara orthology from mouse Akain1, which carries this location by IDA from the same paper. Reason: AKAIN1 is a 69-residue protein with no signal peptide or transmembrane segment and binds soluble PKA regulatory subunits, so a cytosolic location is unsurprising. The transfer is well grounded: its source, mouse Akain1 (G3UWD5), is annotated to GO:0005829 by IDA from PMID:25653177, where endogenous protein was tagged in a mouse line [PMID:25653177 "incorporate the FLAG tag into the C-terminus of the endogenous C18orf42 protein in the mouse neural cell line Neuro2a."]. Supporting Evidence: PMID:25653177 incorporate the FLAG tag into the C-terminus of the endogenous C18orf42 protein in the mouse neural cell line Neuro2a. |
| GO:0008104 intracellular protein localization | IDA PMID:25653177 Hypothetical gene C18orf42 encodes a novel protein kinase A-... | ACCEPT | Summary: Intracellular protein localization. Accepted, deferring to the curator: the localization in question is PKA's, which AKAIN1 acts on by displacing it from AKAPs. Reason: The abstract describes AKAIN1 as acting on where PKA goes, by competing with AKAPs: [PMID:25653177 "that of C18orf42 could block the AKAP-mediated subcellular localization of PKA."]. So AKAIN1 does participate in PKA's intracellular localization, as a negative influence on it. The term carries no direction, and I considered MODIFY to GO:1903828 negative regulation of protein localization. I did not make that change, for a specific reason: the MGI curator reading the same paper for the mouse ortholog kept this very term AND separately added GO:0031333 negative regulation of protein-containing complex assembly (IDA) to capture the disruption. The full-text readers represent this as two statements, not one, so collapsing them would overrule a curation choice I cannot see the basis for. The human-side absence of GO:0031333 is recorded as a knowledge gap instead. Supporting Evidence: PMID:25653177 that of C18orf42 could block the AKAP-mediated subcellular localization of PKA. PMID:25653177 may be a novel PKA signaling gene that serves as an endogenous disruptor peptide for PKA-AKAP interactions. |
| GO:0051018 protein kinase A binding | IDA PMID:25653177 Hypothetical gene C18orf42 encodes a novel protein kinase A-... | MODIFY | Summary: Protein kinase A binding, from the paper that characterised AKAIN1. Correct; the paper specifies regulatory-subunit binding, for which GO has a more precise term. Reason: The binding is to the regulatory subunits specifically, and the paper says so in terms [PMID:25653177 "Immunoprecipitation and pull-down assays showed that C18orf42 binds specifically to the type II regulatory subunits of PKA."]; UniProt records the same partners [file:genes/human/AKAIN1/AKAIN1-uniprot.txt "specifically with RII-regulatory subunits of PKA (PRKAR2A and PRKAR2B)"]. GO has a term for exactly that, GO:0034237 protein kinase A regulatory subunit binding, a direct child of GO:0051018 with no children of its own. It is the term the closest functional analogues carry - AKAP1, AKAP5 and AKAP11, all RII-binding amphipathic-helix proteins, are annotated to it - though not universally, since AKAP7 carries only GO:0051018. This is a refinement in the direction the paper itself states, not a dispute: GO:0051018 is true, just less specific than the evidence. Proposed replacements: protein kinase A regulatory subunit binding Supporting Evidence: PMID:25653177 Immunoprecipitation and pull-down assays showed that C18orf42 binds specifically to the type II regulatory subunits of PKA. file:genes/human/AKAIN1/AKAIN1-uniprot.txt specifically with RII-regulatory subunits of PKA (PRKAR2A and PRKAR2B) file:genes/human/AKAIN1/AKAIN1-deep-research-affinage.md AKAIN1 (C18orf42) is a neural-tissue-enriched protein that engages the cAMP-dependent protein kinase A (PKA) signaling system through direct binding to PKA regulatory subunits |
| GO:0051018 protein kinase A binding | IEA GO_REF:0000120 | MODIFY | Summary: Protein kinase A binding from ARBA, transferred via the mouse ortholog. Same claim as the IDA row; refined the same way so the term carries one action. Reason: Same underlying fact as the IDA row - this ARBA inference derives from the mouse ortholog, whose own annotation comes from the same 2015 paper - so it is refined identically. The binding is to the regulatory subunits specifically, and the paper says so in terms [PMID:25653177 "Immunoprecipitation and pull-down assays showed that C18orf42 binds specifically to the type II regulatory subunits of PKA."]; UniProt records the same partners [file:genes/human/AKAIN1/AKAIN1-uniprot.txt "specifically with RII-regulatory subunits of PKA (PRKAR2A and PRKAR2B)"]. GO has a term for exactly that, GO:0034237 protein kinase A regulatory subunit binding, a direct child of GO:0051018 with no children of its own. It is the term the closest functional analogues carry - AKAP1, AKAP5 and AKAP11, all RII-binding amphipathic-helix proteins, are annotated to it - though not universally, since AKAP7 carries only GO:0051018. This is a refinement in the direction the paper itself states, not a dispute: GO:0051018 is true, just less specific than the evidence. Proposed replacements: protein kinase A regulatory subunit binding Supporting Evidence: PMID:25653177 Immunoprecipitation and pull-down assays showed that C18orf42 binds specifically to the type II regulatory subunits of PKA. |
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Download this section (compressed HTML)Q: Is the HuRI interaction with ROPN1 a docking-domain interaction? ROPN1 has a ropporin dimerization/docking domain and ropporins associate with AKAPs; an RII-binding amphipathic helix would be expected to bind such a domain. If so AKAIN1 may compete with sperm AKAPs as well as with PKA anchoring.
Q: Should human AKAIN1 carry GO:0031333 negative regulation of protein-containing complex assembly, which the mouse ortholog carries by IDA from the same paper?
Q: Does AKAIN1 prefer RIIalpha or RIIbeta, and how does its affinity compare with anchoring AKAPs? Whether it can compete at physiological concentrations depends on both.
Experiment: Knock out AKAIN1 in neurons and test whether PKA localization at AKAP-defined sites increases, which would show displacement happens at endogenous levels.
Experiment: Measure AKAIN1 binding affinity for RIIalpha and RIIbeta dimers by fluorescence polarization against a reference AKAP helix.
Experiment: Test the AKAIN1-ROPN1 interaction directly and map it to the ropporin docking domain and the AKAIN1 amphipathic helix.
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