DDRGK1 / UFBP1 (DDRGK domain-containing protein 1) — research notes

UniProt: Q96HY6 (DDRGK_HUMAN), 314 aa. HGNC:16110. Chromosome 20. Synonyms: UFBP1, Dashurin, C20orf116.

Role in the cascade

DDRGK1 is the obligate cofactor / substrate-adaptor of the UFM1 E3 ligase, a component of the
UREL complex (UFL1 + DDRGK1 + CDK5RAP3). It is a single-pass ER membrane protein (TM 1–28;
cytoplasmic 29–314) that tethers UREL to the ER membrane, restricting ufmylation to ER-docked ribosomes,
and stabilizes UFL1.
- UniProt: "Within the UREL complex, DDRGK1 tethers the complex to the endoplasmic reticulum membrane."
- Binds the E3 ligase UFL1 via its C-terminal region (region 216–314) → core MF GO:0044389 ubiquitin-like protein ligase binding.

UFM1 reader

DDRGK1 has a UFM1-interacting motif (UFIM, residues 195–209) that specifically recognizes ufmylated
RPL26/uL24 → core MF GO:0141185 UFM1-modified protein reader activity [PMID:36121123, PMID:36543799,
PMID:37595036, PMID:38383785, PMID:38383789]. Reading ufmylated RPL26 stabilizes the 60S–UREL association
and drives release/recycling of the 60S subunit from the ER translocon.

Substrate / PTM

DDRGK1 is itself ufmylated at Lys-267 by UFL1; whether this is functional or collateral is unclear (UniProt).

Other roles (downstream / non-core)

• ER stress / UPR: regulates ERN1/IRE1-alpha stability (UFM1-dependent), inhibiting the IRE1 UPR arm [PMID:28128204; PMID:32160526].
• Reticulophagy (CYB5R3 ufmylation) PMID:36543799.
• NF-kappaB: modulates NFKBIA/IkappaB-alpha stability PMID:23675531.
• Cartilage development via SOX9 stabilization; biallelic LoF → Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) PMID:28263186.

Localization

ER membrane (principal). HPA also reports ER, nucleolus; TAS cytoplasm (consistent with the large cytoplasmic domain).

Core function conclusion

Core MFs: GO:0044389 ubiquitin-like protein ligase binding (UFL1 binding/adaptor) and
GO:0141185 UFM1-modified protein reader activity (UFIM). Site: ER membrane.