ABRA, also called STARS (striated muscle activator of Rho signaling) and MS1, is an actin-binding protein enriched in cardiac and skeletal muscle that couples the state of the actin cytoskeleton to muscle gene transcription. Roughly its N-terminal half is intrinsically disordered; the C-terminal half carries two actin-binding regions, of which the first binds filamentous actin with the higher affinity. In striated muscle the protein associates with the sarcomere - reported at the I-band, the Z-disc and the M-line by different studies - and when expressed in non-muscle cells it decorates actin filaments. Functionally it acts upstream of serum response factor rather than on DNA: by binding F-actin, and in a manner requiring RhoA and actin polymerisation, it drives the myocardin-related transcription factors MRTF-A and MRTF-B out of their cytoplasmic G-actin-bound pool and into the nucleus, where they coactivate SRF-dependent transcription of cytoskeletal, contractile and growth genes. Its actin-binding domain is necessary and sufficient for that activity, and knockdown of the endogenous protein lowers SRF activity in differentiated myotubes and cardiac myocytes. The actin-binding LIM proteins ABLIM2 and ABLIM3 bind it and synergistically enhance the SRF response. ABRA is itself a stress-responsive gene: it is induced by MEF2 and by PGC-1-alpha/ERR-alpha, repressed by GATA4, reinforced by an SRF-dependent feed-forward loop on its own promoter, and downregulated post-transcriptionally by miR-628-5p in ageing muscle. Its expression rises with cardiac pressure overload, with resistance and endurance exercise in human skeletal muscle, and in vascular smooth muscle of collateral vessels exposed to elevated fluid shear stress, falling again with de-training. Loss-of-function studies in animals implicate it in cardiac development and contractile function and in fluid-shear-stress-driven arteriogenesis, and gain of function in myotubes promotes myogenic differentiation partly through an MRTF-A-independent route.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030017 sarcomere | IBA GO_REF:0000033 | ACCEPT | Summary: Correct, and at the right level of precision. The PAINT node PTN001100454 sits in PANTHER PTHR22739, whose four reviewed members are all named ABRA (human, mouse, rat, pig) and all fall in the single subfamily PTHR22739:SF20 - a one-to-one ortholog group with no paralog available to contaminate the inference. The WITH/FROM cites RGD:708493, the rat ortholog. Sarcomeric association is the one localisation every primary paper agrees on, but they disagree on where within the sarcomere: the I-band in PMID:11983702, the Z disc in PMID:17415416, and the I-band, Z-disk and M-line together in the PMID:26903873 introduction. Descending to GO:0031674 I band would therefore assert more than the literature settles, and the parent term is the honest choice. The is_active_in qualifier is also right: this is where the F-actin binding is exercised, not merely where the protein is found. Reason: Ortholog-only PANTHER family, consistent sarcomeric localisation across independent reports, and the parent term correctly avoids committing to a sub-compartment the primary literature disputes. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001100454 · ABRA ancestral node (PTHR22739:SF20) SUPPORTS TRANSFER Ortholog-only node; all four reviewed members are ABRA. RGD:708493 · rat Abra SUPPORTS TRANSFER Supporting Evidence: PMID:11983702 STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells, where it activates Rho-signaling events. file:human/ABRA/ABRA-bioinformatics/RESULTS.md All 4 reviewed members of `PTHR22739` are named ABRA (human, mouse, rat, pig) and all fall in the single subfamily `PTHR22739:SF20`. |
| GO:0035025 positive regulation of Rho protein signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Kept, but it is the weakest of the three IBA calls and deserves a caveat rather than a clean pass. The underlying mouse evidence is an IDA from PMID:11983702, whose claim is that STARS "activates Rho-signaling events" in transfected cells and that SRF stimulation "involves Rho GTPase activation". Both observations come from ectopic overexpression, and the later mechanistic paper frames RhoA as a requirement for the STARS effect rather than as its target: PMID:15798203 shows STARS-dependent MRTF import "requires RhoA and actin polymerization". ABRA has no DH/PH or other GEF module, so how it raises Rho signalling output - directly, or as a consequence of changing the actin monomer pool - is unresolved. GO:0035025 is a regulation term and its definition ("any process that activates or increases the frequency, rate or extent of Rho protein signal transduction") accommodates indirect regulation, so the annotation stands as written; the mechanism is what is missing, not the fact. Reason: Directly supported by the source experimental annotation in the mouse ortholog, and the term is a regulation term whose definition permits indirect action. The unresolved question of whether ABRA acts on a Rho GTPase or merely requires one is recorded in suggested_questions rather than being used to reject the term. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2444891 · mouse Abra SUPPORTS TRANSFER Source is an IDA from PMID:11983702; the assay is ectopic overexpression in transfected cells, which is a real caveat on the strength but not on the direction. PANTHER:PTN001100454 · ABRA ancestral node (PTHR22739:SF20) SUPPORTS TRANSFER Supporting Evidence: PMID:11983702 STARS stimulates the transcriptional activity of SRF through a mechanism that requires actin binding and involves Rho GTPase activation. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted. ABRA is not a DNA-binding regulator, and the involved_in qualifier is exactly what conveys that - it participates in a process that raises Pol II transcription without itself being the transcriptional machinery. The route is fully described: PMID:15798203 shows STARS activates SRF by inducing nuclear translocation of the MRTFs, and that endogenous knockdown lowers SRF activity in differentiated C2C12 myotubes and cardiac myocytes, so this is not an overexpression-only claim. The mouse source annotations behind this IBA come from PMID:17194709 and include three IGI rows against Ablim1, Ablim2 and Ablim3, matching that paper's report that the ABLIM proteins synergistically enhance STARS-dependent SRF activation and that ABLIM knockdown blunts SRF-dependent transcription. Reason: Well supported in the mouse ortholog by both gain- and loss-of-function evidence, and the involved_in qualifier correctly represents ABRA as an upstream signalling input to transcription rather than a transcription factor. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2444891 · mouse Abra SUPPORTS TRANSFER Source rows are IDA plus three IGI rows against Ablim1/2/3, all from PMID:17194709. Supporting Evidence: PMID:15798203 Here we show that STARS activates SRF by inducing the nuclear translocation of MRTFs. PMID:17194709 these novel ABLIM proteins strongly bind F-actin, are localized to actin stress fibers, and synergistically enhance STARS-dependent activation of SRF |
| GO:0003779 actin binding | IEA GO_REF:0000120 | MODIFY | Summary: Right activity, avoidably imprecise term. Every characterisation of this protein specifies filaments rather than actin in general: PMID:11983702 reports binding to actin filaments in transfected cells, UniProt's SUBUNIT line says "Binds F-actin", and the DOMAIN line grades the two actin-binding regions by their F-actin affinity. There is no report of ABRA binding monomeric G-actin - indeed the accepted mechanism runs the other way, with ABRA acting on the filamentous pool so that G-actin releases the MRTFs. GO:0051015 actin filament binding is a direct child of GO:0003779 and captures this without any extrapolation. The transfer itself is sound: the WITH/FROM resolves to UniProtKB:Q8BUZ1, the mouse ortholog, whose own actin binding is an IDA from PMID:11983702. Reason: The source evidence and UniProt both specify F-actin, and the child term GO:0051015 states that without adding any claim the literature does not make. Nothing supports G-actin binding, which the parent term leaves open. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER True one-to-one ortholog, IDA for actin binding from PMID:11983702. The transfer is legitimate; only the term granularity is at issue. Proposed replacements: actin filament binding Supporting Evidence: file:human/ABRA/ABRA-uniprot.txt Binds F-actin and ABLIM1, ABLIM2 and ABLIM3. PMID:11983702 STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | MODIFY | Summary: This row exists only because UniProt's SubCell keyword mapping converts the generic "Cytoplasm, cytoskeleton" location statement into the top-level GO cytoskeleton term. It is not wrong, but it is uninformative for a protein whose cytoskeletal association is known to be with actin specifically, and the same record already carries GO:0015629 actin cytoskeleton from two other lines of evidence. Since the underlying UniProt statement is a SubCell mapping rather than a distinct observation, the appropriate fix is to sharpen the term to the actin filament system rather than keep a parent that leaves microtubules and intermediate filaments open. Reason: Bare cytoskeleton is a parent that no evidence for this protein requires; every cytoskeletal observation for ABRA is actin-specific, and the more precise term is already independently supported on the same record. Proposed replacements: actin cytoskeleton Supporting Evidence: file:human/ABRA/ABRA-uniprot.txt Cytoplasm, cytoskeleton {ECO:0000250}. Note=Localized to the I-band of |
| GO:0030017 sarcomere | IEA GO_REF:0000120 | ACCEPT | Summary: The automated-pipeline duplicate of the sarcomere call, transferred from the rat ortholog Q8K4K7 (WITH/FROM also cites ENSRNOP00000010539 and the SubCell identifier SL-0313, all pointing at the same rat record). Same conclusion as the IBA row: correct, and correctly stopped at the sarcomere rather than a disputed sub-compartment. It adds no independent information, but redundant agreement between an automated ortholog transfer and a PAINT inference is not a defect. Reason: Legitimate transfer from a true one-to-one ortholog, consistent with the IBA and ISS rows and with UniProt's own subcellular location statement. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K4K7 · rat Abra SUPPORTS TRANSFER Supporting Evidence: file:human/ABRA/ABRA-uniprot.txt -!- SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere {ECO:0000250}. |
| GO:0035025 positive regulation of Rho protein signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Automated-pipeline duplicate of the Rho signalling call, transferred from mouse Q8BUZ1 with the InterPro Abra signature IPR026111 as a supporting identifier. Same judgement as the IBA row: the term is defensible because it is a regulation term, and the caveat is about mechanism rather than direction. Nothing about routing it through IPR026111 changes the assessment, since that signature is specific to the ABRA family itself rather than to a broader superfamily that might carry unrelated members. Reason: Same evidence as the IBA row, transferred from the same true ortholog through a family-specific InterPro signature; no additional propagation risk. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER InterPro:IPR026111 · Abra family signature SUPPORTS TRANSFER Family-specific signature, not a broad superfamily; no paralog leakage. Supporting Evidence: PMID:11983702 STARS stimulates the transcriptional activity of SRF through a mechanism that requires actin binding and involves Rho GTPase activation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The single WITH/FROM accession resolves to Q6NYC8, human PPP1R18 (phostensin), whose UniProt function is to target protein phosphatase 1 to the F-actin cytoskeleton. Judged against ABRA's own biology this is a compartment-consistent partner rather than screen noise - two F-actin-associated proteins - so there is no basis for calling it an artefact, and it is not treated as one here. Two things nonetheless keep it out of the core set. First, UniProt's "NbExp=3" is not three independent lines of evidence: querying IntAct returns three rows for this pair, all from PMID:32296183, and all three are yeast two-hybrid variants (validated two hybrid, two hybrid array, two hybrid prey pooling) with an IntAct MI score of 0.56. That is one screen plus its internal re-testing, not orthogonal confirmation. Second, the very fact that both proteins bind F-actin supplies a specific alternative explanation that Y2H cannot exclude: yeast actin could bridge two F-actin-binding proteins into a reporter-activating complex without them touching each other. Beyond that, bare protein binding conveys nothing about what ABRA does, and no more informative molecular function term is available for this pair - PPP1R18 is a phosphatase-targeting subunit, so a phosphatase-binding term would misdescribe the relationship. Notably, ABRA's best-supported interactions, with ABLIM2 and ABLIM3 (PMID:17194709), are absent from the human GOA file altogether. Reason: A plausible, compartment-consistent interaction, but supported by a single publication using three variants of one technology, with an unexcluded actin-bridging explanation and no functional follow-up, recorded under a term that carries no functional information. Retained because the interaction may well be real; not promoted to a core function. Supporting Evidence: file:human/ABRA/ABRA-bioinformatics/RESULTS.md Every WITH/FROM protein accession is a genuine one-to-one ortholog of the gene under review (mouse or rat *Abra*), not a paralog |
| GO:0015629 actin cytoskeleton | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection from mouse Q8BUZ1, whose actin cytoskeleton annotation is an IDA from PMID:11983702 - the observation that STARS decorates actin filaments in transfected cells. The transfer is between true one-to-one orthologs. Worth being clear about what this term does and does not say for a muscle protein: in differentiated striated muscle the relevant location is the sarcomere, and the actin cytoskeleton call reflects behaviour in cells where the protein is expressed outside that context. Both are true of ABRA, which is why both terms are retained. Reason: Genuine ortholog transfer from an experimental source, consistent with UniProt's own "Cytoplasm, cytoskeleton" location and with the protein's F-actin binding. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Supporting Evidence: PMID:11983702 STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells |
| GO:0030036 actin cytoskeleton organization | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection of the mouse IDA from PMID:11983702. The process is real - an F-actin-binding protein that alters the filament pool sufficiently to release MRTFs is by definition organising the actin cytoskeleton - and the term is at a defensible level. A more directional term, GO:0030838 positive regulation of actin filament polymerization, is tempting and is what secondary sources state, but the primary abstracts do not support it: PMID:15798203 says the STARS effect requires actin polymerisation, which is not the same as showing that STARS drives it. Left at the parent term rather than manufacturing the sharper claim; the polymerisation question is moved to suggested_experiments. Reason: Supported by an experimental source annotation in a true ortholog, and kept at a granularity the primary literature actually establishes rather than the one review articles assert. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Supporting Evidence: PMID:15798203 The STARS-dependent nuclear import of MRTFs requires RhoA and actin polymerization, and the actin-binding domain of STARS is necessary and sufficient for this activity. |
| GO:0030036 actin cytoskeleton organization | ISS GO_REF:0000024 | ACCEPT | Summary: The curator-asserted (HGNC-UCL) version of the same transfer from mouse Q8BUZ1, made in 2024 and duplicating the Ensembl Compara projection. Same source, same conclusion. Its value over the IEA row is that a curator judged the orthology, which for this family is an easy call - PANTHER PTHR22739 contains a single subfamily and no human paralog. Reason: Curator-asserted ortholog transfer within a one-to-one ortholog group, consistent with the independent Ensembl projection of the same mouse experimental annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Supporting Evidence: file:human/ABRA/ABRA-bioinformatics/RESULTS.md There is no second subfamily and no paralog in the reviewed set, so the IBA annotations from node `PTN001100454` and the ISS transfers are operating inside a one-to-one ortholog group. |
| GO:0005886 plasma membrane | IDA GO_REF:0000054 | MARK AS OVER ANNOTATED | Summary: This is the one annotation on the record that is not a rodent transfer, and it is the one that should not be believed. GO_REF:0000054 is the LIFEdb survey of GFP-tagged proteins expressed in cultured cells - a systematic overexpression screen, not a targeted assay at native levels, so "IDA" overstates what was done. Three independent checks argue against it. UniProt places ABRA at "Cytoplasm, myofibril, sarcomere" and "Cytoplasm, cytoskeleton" and nowhere else. ABRA carries none of the four membrane-targeting UniProt feature classes - Transmembrane, Intramembrane, Signal or Lipidation - queried explicitly for this review, and no membrane-anchoring partner is reported for it, whereas its F-actin binding offers a ready alternative reading of a GFP rim signal as cortical actin. And ABRA is a striated-muscle-enriched protein, so a fusion overexpressed in a non-muscle line has no sarcomere to localise to in the first place. The consequence has already propagated: mouse Abra now carries GO:0005886 twice, by Ensembl Compara IEA (GO_REF:0000107) and by ISO (GO_REF:0000119), and both cite UniProtKB:Q8N0Z2 - so one GFP image in a cell line is now the sole origin of a plasma-membrane annotation in two species. Marked over-annotated rather than removed because the fluorescence may genuinely have been at the cell periphery for the overexpressed fusion; what does not follow is that the endogenous protein resides in the plasma membrane. Reason: A single GFP-fusion overexpression localisation in a non-muscle cell line, contradicted by UniProt's subcellular location, unsupported by any membrane-targeting sequence feature, and readily explained by the protein's known cortical F-actin binding - yet already projected into the mouse record twice. Supporting Evidence: file:human/ABRA/ABRA-bioinformatics/RESULTS.md The single human GFP-overexpression image is the sole origin of a plasma-membrane annotation in two species. file:human/ABRA/ABRA-uniprot.txt -!- SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere {ECO:0000250}. |
| GO:0003779 actin binding | ISS GO_REF:0000024 | MODIFY | Summary: The 2006 HGNC-UCL curator transfer of actin binding from mouse Q8BUZ1, duplicating the later automated row. The orthology judgement is sound; the term is the same avoidable generalisation. Both rows should move to GO:0051015 actin filament binding together, so that the record does not end up asserting filament binding through one line of evidence and unspecified actin binding through another. Reason: Same reasoning as the IEA row: the mouse source evidence and UniProt both specify F-actin, no G-actin binding has been reported, and the two actin-binding rows should be sharpened consistently. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Proposed replacements: actin filament binding Supporting Evidence: file:human/ABRA/ABRA-uniprot.txt The actin-binding domain 1 (ABD1) is intrinsically disordered, |
| GO:0015629 actin cytoskeleton | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-asserted counterpart of the Ensembl Compara projection of the same mouse IDA. Correct and consistent with the rest of the localisation evidence; retained alongside the sarcomere terms because ABRA associates with actin filaments in cells that do not have sarcomeres, and with the sarcomere in cells that do. Reason: Curator ortholog transfer from an experimental mouse annotation, matching UniProt's "Cytoplasm, cytoskeleton" statement and the protein's F-actin binding. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Supporting Evidence: PMID:11983702 STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells |
| GO:0035025 positive regulation of Rho protein signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: Third copy of the Rho signalling call, this time as a 2006 curator transfer from mouse Q8BUZ1. Accepted on the same reasoning as the IBA and IEA rows. It is worth recording that the record's apparent depth here is an illusion: three rows, three evidence codes, one mouse experiment from 2002. Reason: Curator ortholog transfer of the mouse IDA; term stands for the same reasons as the IBA row, with the same open question about mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUZ1 · mouse Abra SUPPORTS TRANSFER Supporting Evidence: PMID:11983702 STARS stimulates the transcriptional activity of SRF through a mechanism that requires actin binding and involves Rho GTPase activation. |
| GO:0030017 sarcomere | ISS GO_REF:0000024 | ACCEPT | Summary: The oldest row on the record (2005), a curator transfer of the sarcomere localisation from the rat ortholog Q8K4K7. Correct, and the origin of the sarcomere call that the later IEA and IBA rows reproduce. Reason: Curator ortholog transfer from rat Abra, consistent with every subsequent line of evidence and with UniProt's subcellular location statement. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K4K7 · rat Abra SUPPORTS TRANSFER Supporting Evidence: file:human/ABRA/ABRA-uniprot.txt -!- SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere {ECO:0000250}. |
| GO:0042307 positive regulation of protein import into nucleus | ISS PMID:15798203 Muscle-specific signaling mechanism that links actin dynamic... | NEW | Summary: Proposed addition. Driving MRTF-A and MRTF-B into the nucleus is the mechanistic centre of what ABRA does, and it is missing from the human record entirely, which jumps from actin binding straight to positive regulation of Pol II transcription with the causal middle absent. UniProt's human FUNCTION line states the step explicitly, and PMID:15798203 demonstrates it in both directions - induction of MRTF nuclear translocation, and reduced SRF activity on knockdown of endogenous STARS. The reason the step never reached human is instructive: mouse Abra does carry an annotation from this paper, but to GO:0006606 protein import into nucleus, which asserts that STARS is itself imported. That is not what the paper shows - STARS causes the MRTFs to be imported - and the wrong-direction term is not one PAINT would propagate as a description of ABRA's role. GO:0042307 is the correctly directed term. Entered as ISS because the demonstration is in the mouse ortholog, with the mouse protein as the supporting entity; the mouse GO:0006606 row should be re-termed at source. Reason: The best-characterised activity of this protein has no human GO annotation, because the mouse source annotation used a term with the wrong direction of causation. Adding the correctly directed regulation term closes the mechanistic gap between ABRA's actin binding and its transcriptional output. Q5 of the reproducible audit makes the basis checkable: mouse Q8BUZ1 carries GO:0006606 as an IDA with an EMPTY WITH/FROM - primary evidence from PMID:15798203, not a transfer from human - and carries no GO:0042307 at all. So this proposal is anchored to a direct assay, and it uses the term the mouse row arguably should have used: ABRA is not the imported cargo, it promotes MRTF-A/B import. Supporting Evidence: PMID:15798203 Here we show that STARS activates SRF by inducing the nuclear translocation of MRTFs. PMID:17415416 activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B file:human/ABRA/ABRA-uniprot.txt -!- FUNCTION: Acts as an activator of serum response factor (SRF)-dependent file:human/ABRA/ABRA-bioinformatics/RESULTS.md | GO:0006606 protein import into nucleus | yes | IDA | PMID:15798203 | *(none)* | |
Loading supporting content…
Download this section (compressed HTML)Q: Does ABRA act on a Rho GTPase, or does it merely require one? GO:0035025 appears three times on this record, all tracing to one 2002 mouse experiment reporting that overexpressed STARS activates Rho-signaling events. ABRA has no DH/PH or other GEF module, and the later mechanistic work frames RhoA as a requirement for the STARS effect rather than its target. Whether ABRA raises Rho-GTP loading directly, or whether the apparent Rho activation is downstream of the change it makes to the actin monomer pool, determines whether the gene's own name describes its molecular function.
Suggested experts: Eric N. Olson, Koichiro Kuwahara
Q: Does the human protein behave like the rodent one? Fourteen of ABRA's sixteen GOA rows are transfers from mouse or rat, and the two that are not are a yeast two-hybrid hit and a GFP-overexpression localisation. No human experiment has established a molecular function, a biological process or a native subcellular location for this protein; the human literature is expression profiling in muscle biopsies. This is not a criticism of the transfers - the orthology is one-to-one and unambiguous - but it means the human record has no independent anchor at all.
Q: Where in the sarcomere is ABRA? The primary reports disagree: the I-band in PMID:11983702, the Z disc in PMID:17415416, and the I-band, Z-disk and M-line together as summarised in PMID:26903873. The parent term sarcomere is used here for that reason, but a definitive answer would allow a much more informative annotation and would constrain which sarcomeric actin pool the protein is reading.
Suggested experts: Nilesh J. Samani
Q: What is the MRTF-A-independent route to myogenic differentiation? Blocking MRTF-A nuclear translocation with CCG-1423 did not abolish the differentiation-promoting effect of STARS overexpression in C2C12 cells, which implies a second output that the canonical STARS-RhoA-MRTF-SRF axis does not explain. Nothing in the current GO record represents it.
Suggested experts: Aaron P. Russell, Severine Lamon
Q: Is the ABRA-PPP1R18 interaction direct? Both proteins bind F-actin, and all the evidence is yeast two-hybrid from a single publication, so bridging by endogenous yeast actin is a live alternative. If the interaction is real it would be interesting - it would put a protein phosphatase 1 targeting subunit next to the actin sensor that controls MRTF release - but a Y2H hit alone does not establish it.
Q: Should ABRA's UniProt keywords be corrected? The entry carries Protein transport, Translocation and Transport, which appear to be a literal reading of the FUNCTION line's "inducing nuclear translocation of MKL1 or MKL2". ABRA is not a transporter and does not carry cargo; it regulates the localisation of other proteins. These keywords previously generated a GO:0015031 protein transport annotation through the SwissProt keyword pipeline.
Experiment: Measure RhoA-GTP by rhotekin pulldown in muscle cells after acute, near-physiological induction of ABRA, and compare with an actin-binding-deficient mutant and with conditions where the actin pool is manipulated independently (latrunculin, jasplakinolide). If Rho activation requires an intact actin-binding domain and is reproduced by pharmacological actin polymerisation alone, ABRA is not acting on Rho; if the mutant still activates Rho, it is. Either result settles whether GO:0035025 describes a direct or a downstream effect.
Hypothesis: ABRA increases Rho-GTP loading directly, rather than Rho signalling being a consequence of its effect on the actin pool.
Type: biochemistry and cell signalling
Experiment: Localise endogenously tagged ABRA in human cardiomyocytes or myotubes by imaging and by membrane/cytoskeletal fractionation, alongside the LIFEdb-style overexpressed GFP fusion in a non-muscle line as a side-by-side control. This directly tests whether the plasma-membrane call reflects the protein or the assay, and would also resolve the sarcomeric sub-compartment. Because that call has already been projected into the mouse record twice, correcting it at source would clear annotations in two species.
Hypothesis: ABRA is not at the plasma membrane at endogenous levels in muscle.
Type: cell biology
Experiment: Run pyrene-actin polymerisation assays with purified ABRA and with each of its two actin-binding regions separately, and measure the G-actin/F-actin ratio in cells on ABRA induction. A positive result would justify GO:0030838 positive regulation of actin filament polymerization, which is currently asserted by review articles but not, so far as the primary abstracts go, demonstrated.
Hypothesis: ABRA promotes actin filament polymerisation, rather than only requiring it.
Type: in vitro biochemistry
Experiment: Repeat the C2C12 differentiation experiment with ABRA induction under MRTF-A/MRTF-B double knockdown rather than pharmacological inhibition, and profile the transcriptome to separate SRF target genes from the residual response. Any coherent residual programme identifies the second output and would be the first genuinely new biological process annotation available for this gene.
Hypothesis: The MRTF-A-independent contribution of ABRA to myogenic differentiation runs through a distinct effector.
Type: functional genomics
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)