PROSITE documentation PDOC51140
CUE domain profile


The Coupling of Ubiquitin conjugation to ER degradation or CUE domain is a ~44 residue ubiquitin binding domain, present in eukaryotic proteins of trafficking and ubiquitination pathways. Ubiquitin is a 76 amino acid polypeptide that can be attached to proteins to alter their activity or location (see <PDOC00271>). Monoubiquitination and the addition of polyubiquitin chains are important cellular regulatory signals. The CUE domain was named after baker's yeast Cue1 protein [1]. Some domains which can occur in combination with the CUE domain are the RING-type zinc finger (see <PDOC00449>), the Smr domain (see <PDOC50828>) or the C2 domain (see <PDOC00380>). CUE domains can bind monoubiquitin and can be required for ubiquitination of the protein in which they are found [2,3,4].

The 3D structure of the CUE domain comprises three α helices arranged in a bundle (see <PDB:1OTR>), similar to the fold of the UBA domain (see <PDOC50030>). The binding surface is a hydrophobic patch that is complementary to the ubiquitin hydrophobic surface. The CUE domain contains two conserved motifs that bind ubiquitin, i.e. (MF)P, C-terminal to the first helix, and a di-leucine-like motif in the third helix.

Some proteins known to contain a CUE domain:

  • Yeast Cue1 (YMR264W) protein, which recruits the ubiquitin-conjugating enzyme Ubc7p to the endoplasmic reticulum (ER), where it is essential for the degradation of misfolded proteins. The Cue1 CUE domain lacks parts of the motifs and shows a relatively low affinity for ubiquitin [2].
  • Yeast Cue2, Cue3 (YGL110C), Cue4 (YML101C) and Cue5 (YOR042w) proteins, which have different ubiquitin-binding affinities [2]. Cue2 contains a tandem of two ubiquitin binding CUE domains near its N-terminus.
  • Yeast Def1 (YKL054C) protein, which is involved in ubiquitination of RNA polymerase II and mediating its degradation through interaction with Rad26.
  • Fungal Vacuolar Protein Sorting-associated protein Vps9, a guanine nucleotide exchange factor for the Rab-like GTPase Vps21. Vps9 is needed for the transport of proteins from biosynthetic and endocytic pathways into the vacuole. Its C-terminal CUE domain forms a dimer which binds a single ubiquitin molecule.
  • Mammalian Toll-interacting protein tollip and TAB2, proteins involved in signaling from the interleukin-1 receptor.
  • Human autocrine motility factor receptor (AMFR), a cytokine receptor that regulates tumor cell motility and promotes metastasis. AMFR is conserved among metazoans.
  • Human ancient ubiquitous protein 1 (AUP1), involved in integrin signaling. Aup1 is conserved among metazoans.
  • Japanese pufferfish BAW (Between AKAP84 and WSBB1 genes) protein.

The profile we developed covers the entire CUE domain.

Last update:

July 2005 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

CUE, PS51140; CUE domain profile  (MATRIX)


1AuthorsPonting C.P.
TitleProteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction.
SourceBiochem. J. 351:527-535(2000).
PubMed ID11023840

2AuthorsShih S.C. Prag G. Francis S.A. Sutanto M.A. Hurley J.H. Hicke L.
TitleA ubiquitin-binding motif required for intramolecular monoubiquitylation, the CUE domain.
SourceEMBO J. 22:1273-1281(2003).
PubMed ID12628920

3AuthorsPrag G. Misra S. Jones E.A. Ghirlando R. Davies B.A. Horazdovsky B.F. Hurley J.H.
TitleMechanism of ubiquitin recognition by the CUE domain of Vps9p.
SourceCell 113:609-620(2003).
PubMed ID12787502

4AuthorsKang R.S. Daniels C.M. Francis S.A. Shih S.C. Salerno W.J. Hicke L. Radhakrishnan I.
TitleSolution structure of a CUE-ubiquitin complex reveals a conserved mode of ubiquitin binding.
SourceCell 113:621-630(2003).
PubMed ID12787503

PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see prosite_license.html.


View entry in original PROSITE document format
View entry in raw text format (no links)