|PROSITE documentation PDOC51997|
The up-frameshift protein 1 (Upf1 also known as Regulator of nonsense transcripts, Rent1) is an essential eukaryotic RNA helicase that plays a key role in various mRNA degradation pathways, notably nonsense-mediated mRNA decay (NMD). In combination with Upf2 and Upf3, it forms part of the surveillance complex that detects mRNAs containing premature stop codons and triggers their degradation in all organisms studied from yeast to human. In the complex, Upf1 exhibits ATPase activity that is essential for NMD. Upf2 and Upf3 are nonenzymatic components of the surveillance complex that stimulate the activity of Upf1 [1,2].
In its N-terminal region, Upf1 has a conserved cysteine-histidine-rich (CH-rich) domain, while centrally it possesses the seven conserved motifs characteristic of eukaryotic group I RNA helicases. The Upf1 CH-rich domain has a cis-inhibitory effect on the ATPase activity and is also the region that binds Upf2. Upon binding to Upf2, the regulatory CH-rich domain of Upf1 undergoes a large conformational change, causing the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity. Formation of the surveillance complex thus modifies the RNA binding properties and the catalytic activity of Upf1, causing it to switch from an RNA-clamping mode to an RNA-unwinding mode [1,2].
The highly conserved CH-rich domain is a unique combination of three zinc-binding motifs arranged into two tandem modules related to the RING-box and U-box domains of ubiquitin ligases. The main feature of the structure (see <PDB:2IYK>) is a central, pseudo-twofold symmetric, four-stranded antiparallel β-sheet (strands β1-β4) with symmetric flanking loops L1 and L6. While L1 is involved in coordinating Zn1, L6 is stabilized by Zn3. The zinc ions are coordinated via different combinations of histidine and cysteine residues and serve a structural role in maintaining the fold of the CH domain. Zn1 is coordinated by three cysteines and one histidine within a treble clef zinc-finger-like motif. Most Upf1 homologs have the conventional C2H2 ligands for Zn2 binding. Only in vertebrates has C2H2 evolved to become CSHC, the structure suggesting that Ser is actually a zinc ligand. Finally, Zn3 is coordinated within a second treble-clef zinc-finger motif. All the zinc coordinating residues are absolutely conserved among known Upf1 homologs, suggesting that the zinc atoms are crucial for UPF1 structure and hence function [1,2].
The profile we developed covers the entire Upf1 CH-rich domain.Last update:
April 2022 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|1||Authors||Kadlec J. Guilligay D. Ravelli R.B. Cusack S.|
|Title||Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1.|
|2||Authors||Chakrabarti S. Jayachandran U. Bonneau F. Fiorini F. Basquin C. Domcke S. Le Hir H. Conti E.|
|Title||Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2.|
|Source||Mol. Cell. 41:693-703(2011).|