esrp1

UniProt ID: A0A4W3GVU1
Organism: Callorhinchus milii
Review Status: DRAFT
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Gene Description

ESRP1 (Epithelial Splicing Regulatory Protein 1) is an RNA-binding protein belonging to the ESRP family within the broader heterogeneous nuclear ribonucleoprotein (hnRNP) superfamily. The protein contains three RNA recognition motif (RRM) domains that bind UGG-rich and GGU-rich RNA sequences to regulate alternative pre-mRNA splicing. ESRP1 functions primarily in the nucleus as a master regulator of an epithelial-specific splicing program, controlling exon inclusion or exclusion in a position-dependent manner across hundreds of target genes involved in cell-cell adhesion, cell polarity, tight junctions, and cytoskeletal organization. Its best-characterized target is FGFR2, where it promotes inclusion of the epithelial exon IIIb and repression of the mesenchymal exon IIIc, thereby switching receptor ligand specificity. ESRP1 also has cytoplasmic roles in post-transcriptional regulation including mRNA stability and circular RNA biogenesis. In mammals, ESRP1 is essential for craniofacial and limb development and plays a central inhibitory role in epithelial-mesenchymal transition (EMT). The Callorhinchus milii ortholog is inferred to share these conserved functions based on high RRM domain sequence identity across vertebrates and invertebrates.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0003676 nucleic acid binding
IEA
GO_REF:0000002 		MODIFY
Summary: ESRP1 is indeed a nucleic acid binding protein, but this term is overly broad. The protein specifically binds RNA via its three RRM domains, recognizing UGG-rich and GGU-rich sequences in pre-mRNA transcripts. The more specific term GO:0003723 (RNA binding) is already annotated and captures the actual binding specificity of this protein. Nucleic acid binding adds no additional information beyond what RNA binding already provides and obscures the RNA specificity of ESRP1.
Reason: The term is too general. ESRP1 binds RNA, not DNA. The InterPro domains (RBD superfamily, RRM domain) that generated this annotation are RNA-binding domains, and the more precise GO:0003723 (RNA binding) is already present. An even more specific term such as GO:0003729 (mRNA binding) would better reflect ESRP1's function as a pre-mRNA splicing regulator.
Proposed replacements: mRNA binding
Supporting Evidence:
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-deep-research-falcon.md
ESRP1 functions as a sequence-specific RNA-binding protein that regulates alternative splicing
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt
RRM domain-containing protein
GO:0003723 RNA binding
IEA
GO_REF:0000120 		ACCEPT
Summary: ESRP1 is an RNA-binding protein with three RRM domains that bind UGG/GGU-rich motifs in pre-mRNA. Structural studies of the qRRM2 domain show guanines inserted into aromatic pockets for sequence-specific RNA recognition. RNA binding is a core molecular function of ESRP1 and is well supported by domain architecture, structural data from orthologs, and the known mechanism of alternative splicing regulation.
Reason: RNA binding is a central and well-established molecular function of ESRP proteins. The three RRM domains are highly conserved across vertebrates and invertebrates, and structural and biochemical evidence from mammalian orthologs confirms sequence-specific RNA binding.
Supporting Evidence:
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt
RNA-binding
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-deep-research-falcon.md
X-ray crystal structure of the ESRP1 qRRM2 domain reveals it binds to GGU motifs
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: ESRP1 localizes to the nucleus where it functions as a pre-mRNA splicing regulator. The protein contains a putative nuclear localization sequence (pNLS). Nuclear localization is the primary site of its splicing regulatory activity. ESRP1 also exists as cytoplasmic isoforms generated by alternative splicing at exon 12, but the nucleus is the primary functional location.
Reason: Nuclear localization is well established for ESRP1 and is where it carries out its primary function of alternative splicing regulation. The UniProt subcellular location annotation and the ARBA evidence both support nuclear localization.
Supporting Evidence:
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt
Nucleus
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-deep-research-falcon.md
Contains a putative nuclear localization sequence (pNLS)
GO:0048024 regulation of mRNA splicing, via spliceosome
IEA
GO_REF:0000002 		NEW
Summary: ESRP1 is a well-characterized regulator of alternative pre-mRNA splicing. It does not catalyze splicing itself but modulates spliceosome recruitment and activity by binding to cis-regulatory elements (ISE/ISS) in pre-mRNA. ESRP1 controls the inclusion or exclusion of specific exons in a position-dependent manner across hundreds of target transcripts. This biological process annotation accurately captures the gene's primary biological role.
Reason: ESRP1 is a splicing regulator and this process term directly reflects its core biological role. The UniProt entry lists mRNA processing and mRNA splicing as keywords, and the deep research literature extensively documents ESRP1's function in regulating alternative splicing via the spliceosome.
Supporting Evidence:
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt
mRNA splicing
file:CALMI/A0A4W3GVU1/A0A4W3GVU1-deep-research-falcon.md
ESRP1 functions as a sequence-specific RNA-binding protein that regulates alternative splicing

Core Functions

ESRP1 binds pre-mRNA transcripts via three RRM domains that recognize UGG/GGU-rich sequences, acting as a sequence-specific mRNA binding protein that regulates alternative splicing of epithelial-specific gene programs.

Molecular Function:
mRNA binding
Directly Involved In:
regulation of mRNA splicing, via spliceosome
Cellular Locations:
nucleus
Supporting Evidence:
  • file:CALMI/A0A4W3GVU1/A0A4W3GVU1-deep-research-falcon.md
    ESRP1 functions as a sequence-specific RNA-binding protein that regulates alternative splicing
  • file:CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt
    RRM domain-containing protein

References

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External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · A0A4W3GVU1-protnlm-predictions-review.yaml · Review status: COMPLETE

The ESRP1-family assignment and retention of the characterized nuclear-localization peptide support the existing nuclear annotation.

Source documents: genes/CALMI/A0A4W3GVU1/A0A4W3GVU1-uniprot.txt · genes/CALMI/A0A4W3GVU1/A0A4W3GVU1-goa.tsv · publications/PMID_28634384.md · genes/CALMI/A0A4W3GVU1/A0A4W3GVU1-hypotheses/prediction-nucleus-localization/openscientist.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0005634 nucleus GO_CC
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target is an ESRP1-family RNA-binding protein with an ESRP1 RRM assignment and the sequence GLSPPPCKLPCLSPP. Experiments on mammalian ESRP1 identify this peptide region as sufficient for nuclear localization and show that splice isoforms lacking CKLP can instead be cytoplasmic (PMID:28634384). Retention of the nuclear peptide supports transfer to this Callorhinchus sequence, without claiming that every ESRP1 isoform is nuclear. The exact nucleus annotation is already present in both cached UniProt and GOA.
Supporting Evidence:

Deep Research

Falcon

(A0A4W3GVU1-deep-research-falcon.md)

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OpenScientist

(A0A4W3GVU1-hypotheses/prediction-nucleus-localization/openscientist.md)

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📄 View Raw YAML

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