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.