Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
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Human Protein Atlas immunofluorescence, reliability Enhanced for AHNAK2, main location Cytosol and additional location Plasma membrane, with no nuclear compartment called. These are the only two GOA rows on AHNAK2 that rest on a measurement of the human protein.
Electronic Gene Ontology annotations created by ARBA machine learning models
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Supplies the cytoplasm and plasma membrane IEA rows via ARBA00026971 and ARBA00027801. Neither rule's published condition sets - 2388 and 686 respectively, over InterPro, PANTHER, FunFam and taxon - mentions any AHNAK2 signature.
AHNAK2 bioinformatics checks for GOA propagation and partner provenance
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Resolving the IBA WITH/FROM donor sets found that AHNAK2's ortholog is absent from the nucleus and RNA-splicing donor sets.
"**The AHNAK2 ortholog is absent from two of the three IBA donor sets.**"
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The current public ARBA rules for cytoplasm and plasma membrane do not expose a condition set that matches any AHNAK2 signature.
"**Not one condition set in either rule mentions any of AHNAK2's six
signatures**"
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AHNAK2 has many IntAct records, but none match the two protein-binding partners imported by GOA from PMID:17185750.
"GOA's only two `GO:0005515` rows name `O75923` (DYSF) and `Q9NZM1` (MYOF), and
**neither appears anywhere in IntAct's AHNAK2 record**."
AHNAK, a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration.
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Identifies AHNAK as a dysferlin-interacting protein by co-IP/MS and maps the binding sites to dysferlin's C2A domain and AHNAK's carboxyterminal domain by GST pull-down. The abstract's myoferlin result is likewise attributed to AHNAK.
"As
expected, the N-terminal domain of myoferlin also interacts with the
carboxyterminal domain of AHNAK."
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Places dysferlin and AHNAK at the sarcolemmal membrane and T-tubules of normal skeletal muscle. This is the observation behind AHNAK2's T-tubule and sarcolemma NAS rows, and the abstract attributes it to AHNAK.
"In normal skeletal muscle, dysferlin and AHNAK
colocalize at the sarcolemmal membrane and T-tubules."
Periaxin and AHNAK nucleoprotein 2 form intertwined homodimers through domain swapping.
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Crystal structures of the PDZ-like domains of periaxin and AHNAK2 (PDB 4CN0, 1.75 A, chains A and B, residues 108-203) showing intertwined domain-swapped homodimers, with a six-stranded antiparallel beta sheet built from alternating strands of the two chains.
"The unique
intertwined, domain-swapped dimers provide a structural basis for the
homodimerization of both proteins."
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The AHNAK2 PDZ domain crystallised with a bound class III ligand peptide in a preformed pocket, with unusual features including two salt bridges and weak recognition of the peptide C terminus.
"The AHNAK2 PDZ domain structure contains a bound class III ligand peptide."
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Frames both proteins as scaffolds in complexes linking the extracellular matrix to the cytoskeletal network, with tight homodimerisation as the central element.
"Tight homodimerization may be central to the scaffolding functions of
PRX and AHNAK2 in molecular complexes linking the extracellular matrix to the
cytoskeletal network."
AHNAK1 and AHNAK2 are costameric proteins: AHNAK1 affects transverse skeletal muscle fiber stiffness.
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Uses antibodies specific for AHNAK1 and AHNAK2 - the only AHNAK2-specific localisation reagents used in any study reviewed here - and places both proteins in the costameric network of mouse skeletal muscle by co-localisation with vinculin.
"Co-localization of AHNAK1 and AHNAK2 with vinculin clearly
demonstrates that both proteins are components of the costameric network."
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Reports no AHNAK signal in the T-tubule system, in contrast to the same study's positive costameric result.
"In
contrast, no AHNAK expression was detected in the T-tubule system."
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A laser wounding assay on AHNAK1-deficient fibres found no membrane-repair role for AHNAK1, and AHNAK1-null fibres were significantly stiffer by atomic force microscopy. Both results concern AHNAK1, not AHNAK2.
"A laser
wounding assay with AHNAK1-deficient fibers suggests that AHNAK1 is not involved
in membrane repair."
The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells.
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The AHNAK2 discovery paper - AHNAK2 was found as the protein still present in AHNAK-null mice.
"Homozygous knockouts showed no obvious phenotype, but revealed instead a second
AHNAK-like molecule, provisionally designated AHNAK2."
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Its localisation of AHNAK2 is hedged in the abstract itself and rests on cosedimentation with a dihydropyridine-receptor-containing vesicle fraction rather than on an AHNAK2-specific reagent. This is the only independent T-tubule evidence for AHNAK2, and it is in cardiomyocytes.
"The localization of the AHNAKs in
close proximity to transverse tubule membranes and Z-band regions of cardiac
sarcomeres raise the possibility that they might be involved in regulating
excitation/contraction coupling of cardiomyocytes"
Self-regulated alternative splicing at the AHNAK locus.
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Demonstrates a cis, locus-autonomous mechanism: a small AHNAK isoform accumulates during muscle differentiation and feeds back on the splicing of its own locus. This is the sole experimental basis of AHNAK2's GO:0043484 IBA row, via mouse Ahnak.
"During muscle differentiation
the small AHNAK is strongly increased, thereby establishing a positive feedback
loop to regulate mRNA splicing of its own locus."
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Shows the same for a 17-kDa periaxin isoform on the periaxin locus, and locates the nuclear pool of these proteins in the small isoform rather than the giant chain.
"A small 17-kDa isoform of
Periaxin similarly traffics between the cytoplasm and the nucleus to regulate
mRNA splicing."
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States that the AHNAK gene architecture - one 17-kb exon flanked by multiple small exons - is shared with AHNAK2 and periaxin. This is what makes the PAINT transfer to AHNAK2 a reasonable inference rather than a careless one.
"This genetic structure is shared by AHNAK2 and Periaxin,
which share a common ancestor."
AHNAK2 Participates in the Stress-Induced Nonclassical FGF1 Secretion Pathway.
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Identifies a heat-shock-dependent association between FGF1 and AHNAK2 by immunoprecipitation mass spectrometry, confirmed reciprocally with anti-V5 and anti-HA antibodies on an adenovirally expressed V5-tagged C-terminal fragment of human AHNAK2 in NIH 3T3 cells.
"The heat shock-dependent association of FGF1 with
the large protein AHNAK2 was observed."
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shRNA depletion of AHNAK2 drastically reduces stress-induced FGF1 export without affecting spontaneous FGF2 export or Notch-inhibition-induced FGF1 release - a specificity control that distinguishes this from a general secretory defect.
"Depletion of AHNAK2 resulted in a drastic decrease of
stress-induced FGF1 export but did not affect spontaneous FGF2 export and FGF1
release induced by the inhibition of Notch signaling."
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The knockdown constructs target mouse AHNAK2, which is why the human annotation proposed here is ISS rather than IMP.
"Genetic constructs pGFP-V-RS expressing shRNAs that suppress the expression of mouse AHNAK2 were obtained from Origene (Rockville, MD)."
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The authors record that commercially available anti-AHNAK2 antibodies could not detect the protein reliably, which is why a tagged fragment was used and why the evidence is weaker than the headline suggests.
"commercially available anti-AHNAK2 antibodies failed to reliably detect AHNAK2 both in immunoblotting and immunofluorescence"
Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family.
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Maps an autosomal recessive CMT locus to chromosome 14q32 in a consanguineous family and identifies two segregating AHNAK2 variants, p.T40P and p.H915Y, with reduced AHNAK2 mRNA and protein in patient fibroblasts. p.T40P lies N-terminal to the PDZ domain at 112-193.
"Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed
significantly reduced mRNA and protein levels."
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Its mechanistic framing rests on an asserted direct AHNAK2-periaxin interaction, stated as background rather than measured here, and its own conclusion is hedged.
"The altered expression of mutant AHNAK2 may disrupt the
AHNAK2-PRX interaction in which one of its known functions is to regulate
myelination."
The Obscure Potential of AHNAK2.
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A dedicated AHNAK2 review, used as a secondary source for corpus-level statements and to locate primary papers. It records how little functional work exists on the protein, and states the cardiac-versus-skeletal T-tubule discrepancy directly in its text.
"Little work has been done in exploring the function and
relation AHNAK2 has with cancer"