Overview
| Uniprot ID | Q96HY6 |
|---|
| Protein Name | DDRGK domain-containing protein 1 |
|---|
| Gene Name | DDRGK1 |
|---|
| Organism | Homo sapiens |
|---|
Kla Sites from experimental identification
| Position |
Flanking peptide |
| 191 |
REHEEYLKLKEAFVV |
Function
Component of the UFM1 ribosome E3 ligase (UREL) complex, a multiprotein complex that catalyzes ufmylation of endoplasmic reticulum-docked proteins (PubMed:30626644, PubMed:32160526, PubMed:35753586, PubMed:36121123, PubMed:36543799, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789). The UREL complex plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit of the 60S ribosome following ribosome dissociation: ufmylation weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37595036, PubMed:38383785, PubMed:38383789). Within the UREL complex, DDRGK1 tethers the complex to the endoplasmic reticulum membrane to restrict its activity to endoplasmic reticulum-docked ribosomes and acts as an ufmylation 'reader': following RPL26/uL24 ufmylation, DDRGK1 specifically binds to ufmylated RPL26/uL24 via its UFIM motif, resulting in stable association between the 60S ribosome and the UREL complex, followed by dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane (PubMed:36121123, PubMed:37595036, PubMed:38383785, PubMed:38383789). The UREL complex is also involved in reticulophagy in response to endoplasmic reticulum stress by promoting ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:32160526, PubMed:36543799). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability (PubMed:28128204, PubMed:32160526). Acts as a regulator of immunity by promoting differentiation of B-cells into plasma cells: acts by promoting expansion of the endoplasmic reticulum and regulating the unfolded protein response (UPR) (By similarity). May also be required for TRIP4 ufmylation (PubMed:25219498). May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B (PubMed:23675531). Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator (PubMed:28263186). Required for stabilization and ufmylation of ATG9A (By similarity)
Protein Sequence
10
MVAPVWYLVA
20
AALLVGFILF
30
LTRSRGRAAS
40
AGQEPLHNEE
50
LAGAGRVAQP
60
GPLEPEEPRA
70
GGRPRRRRDL
80
GSRLQAQRRA
90
QRVAWAEADE
100
NEEEAVILAQ
110
EEEGVEKPAE
120
THLSGKIGAK
130
KLRKLEEKQA
140
RKAQREAEEA
150
EREERKRLES
160
QREAEWKKEE
170
ERLRLEEEQK
180
EEEERKAREE
190
QAQREHEEYL
200
KLKEAFVVEE
210
EGVGETMTEE
220
QSQSFLTEFI
230
NYIKQSKVVL
240
LEDLASQVGL
250
RTQDTINRIQ
260
DLLAEGTITG
270
VIDDRGKFIY
280
ITPEELAAVA
290
NFIRQRGRVS
300
IAELAQASNS
310
LIAWGRESPA
QAPA
Gene Ontology
| Classification |
GO ID |
Description |
| Cellular Component |
GO:0005737 |
cytoplasm |
| Cellular Component |
GO:0005783 |
endoplasmic reticulum |
| Cellular Component |
GO:0005789 |
endoplasmic reticulum membrane |
| Molecular Function |
GO:0044389 |
ubiquitin-like protein ligase binding |
| Molecular Function |
GO:0141185 |
UFM1-modified protein reader activity |
| Biological Process |
GO:0051216 |
cartilage development |
| Biological Process |
GO:0043066 |
negative regulation of apoptotic process |
| Biological Process |
GO:0010629 |
negative regulation of gene expression |
| Biological Process |
GO:1903895 |
negative regulation of IRE1-mediated unfolded protein response |
| Biological Process |
GO:1903898 |
negative regulation of PERK-mediated unfolded protein response |
| Biological Process |
GO:0032435 |
negative regulation of proteasomal ubiquitin-dependent protein catabolic process |
| Biological Process |
GO:0043123 |
positive regulation of canonical NF-kappaB signal transduction |
| Biological Process |
GO:1902808 |
positive regulation of cell cycle G1/S phase transition |
| Biological Process |
GO:0030335 |
positive regulation of cell migration |
| Biological Process |
GO:0008284 |
positive regulation of cell population proliferation |
| Biological Process |
GO:0010628 |
positive regulation of gene expression |
| Biological Process |
GO:1903721 |
positive regulation of I-kappaB phosphorylation |
| Biological Process |
GO:1900100 |
positive regulation of plasma cell differentiation |
| Biological Process |
GO:1901800 |
positive regulation of proteasomal protein catabolic process |
| Biological Process |
GO:0032436 |
positive regulation of proteasomal ubiquitin-dependent protein catabolic process |
| Biological Process |
GO:1905552 |
positive regulation of protein localization to endoplasmic reticulum |
| Biological Process |
GO:1903052 |
positive regulation of proteolysis involved in protein catabolic process |
| Biological Process |
GO:0140501 |
positive regulation of reticulophagy |
| Biological Process |
GO:0045944 |
positive regulation of transcription by RNA polymerase II |
| Biological Process |
GO:1990592 |
protein K69-linked ufmylation |
| Biological Process |
GO:0070972 |
protein localization to endoplasmic reticulum |
| Biological Process |
GO:0071569 |
protein ufmylation |
| Biological Process |
GO:0033146 |
regulation of intracellular estrogen receptor signaling pathway |
| Biological Process |
GO:0031647 |
regulation of protein stability |
| Biological Process |
GO:0072344 |
rescue of stalled cytosolic ribosome |
| Biological Process |
GO:0034976 |
response to endoplasmic reticulum stress |
| Biological Process |
GO:0061709 |
reticulophagy |
| Biological Process |
GO:0032790 |
ribosome disassembly |
Reference
[1] Yang Z, Yan C, Ma J, Peng P, Ren X et al.. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.. Nat Metab 5(1):61-79. 2023 Jan. PMID: 36593272.