# GIGYF1 (O75420) research notes

GRB10-interacting GYF protein 1 (PERQ1). Paralog of GIGYF2. Member of the GIGYF family.

## Core function
GIGYF1 is a scaffolding/adaptor protein that nucleates a translational repression and
co-translational mRNA decay module together with the non-canonical cap-binding protein
4EHP/EIF4E2, the DEAD-box helicase DDX6, and the collision sensor E3 ligase ZNF598.

- The 4EHP-GIGYF1/2 complex triggers co-translational mRNA decay on transcripts with
  ribosome pausing/stalling: [PMID:33053355 "Here, we show that 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with prominent ribosome pausing."] and [PMID:33053355 "4EHP-GIGYF1/2 complexes fail to reduce mRNA levels in the absence of ribosome stalling or upon disruption of their interaction with the cap structure, DDX6, and ZNF598."]
- Co-translational binding of GIGYF1/2 marks transcripts with perturbed elongation for decay:
  [PMID:33053355 "co-translational binding of GIGYF1/2 to the mRNA marks transcripts with perturbed elongation to decay."]
- GIGYF proteins have an N-terminal 4EHP-binding region and a central GYF domain that mediates
  interaction with ZNF598, TTP, or TNRC6 proteins: [PMID:31439631 "These proteins possess an N-terminal 4EHP-binding region (4EHP-BR) and a central compacted GYF domain ... that mediates the interaction with ZNF598, tristetraprolin (TTP), or the microRNA (miRNA)-induced silencing complex-associated TNRC6 proteins"]
- GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6;
  4EHP-GIGYF-DDX6 assembly is required for TTP-mediated repression of an AU-rich mRNA:
  [PMID:31439631 "we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6" ; "4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA"]
- DDX6 interaction confirmed for GIGYF1 with mutagenesis of W294/F306/F312 abolishing it
  (UniProt, PMID:31439631).

## IGF/GRB10 signaling (legacy function)
Originally identified via GRB10 as a modulator of IGF-I receptor signaling
[PMID:12771153 "Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling."]. UniProt FUNCTION: "May act
cooperatively with GRB10 to regulate tyrosine kinase receptor signaling. May increase IGF1
receptor phosphorylation". This is the basis of the IBA GO:0048009 (IGF receptor signaling)
annotation. It is a real but secondary/less-characterized role relative to the translational
repression module.

## ComplexPortal
- CPX-2336: 4EHP-GIGYF1 co-translational mRNA decay complex, ZNF598 variant
- CPX-2342: 4EHP-GIGYF1 co-translational mRNA decay complex, DDX6 variant
Basis of NAS GO:1990261 (pre-mRNA catabolic process) and IDA GO:0032991 (complex).

## Annotation assessment
- GO:0045947 negative regulation of translational initiation (IBA): ACCEPT, core. 4EHP binding
  represses cap-dependent initiation.
- GO:0005829 cytosol (IBA): ACCEPT.
- GO:0048009 IGF receptor signaling pathway (IBA): KEEP_AS_NON_CORE — legacy GRB10/IGF role.
- protein binding (IPI) x many: mostly interactome screens. The functionally meaningful one is
  EIF4E2/DDX6/ZNF598. PMID:31439631 (DDX6) -> capture as eIF4E2/DDX6 binding informative MF;
  others KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED (HT screens).
- GO:1990261 pre-mRNA catabolic process (NAS, ComplexPortal): the complex mediates
  co-translational mRNA decay; MODIFY toward mRNA catabolic / translation-coupled decay would be
  more accurate but pre-mRNA catabolic is arguably wrong (it's mature mRNA). Keep as
  KEEP_AS_NON_CORE / note imprecision.
- GO:0032991 protein-containing complex (IDA): uninformative top-level term -> KEEP_AS_NON_CORE.

## Core MF/BP for review
- MF: GO:0008190 eukaryotic initiation factor 4E binding (binds 4EHP/EIF4E2) — well supported.
- BP: GO:0045947 negative regulation of translational initiation; GO:0017148 negative regulation
  of translation; co-translational mRNA decay (GO:0006515 / mRNA catabolic).