PROSITE documentation PDOC52088

UPF1-type helicase core domain profile

Helicases use ATP to bind or remodel nucleic acids, nucleic acid-protein complexes, or both. All forms of cellular life and many viruses encode helicases, which constitute one of the largest classes of enzymes. Virtually all biological processes involving DNA or RNA employ one or more helicases. Helicases have been classified into six superfamilies (SF1-SF6) and subsequent subfamilies. SF1 and SF2 are the largest groups of RNA and DNA helicases generally acting as monomers or dimers while SF3-SF6 encompass multimeric ring-shaped helicases. One of the most notable SF1 and SF2 helicase signatures are the at least 12 characteristic sequence motifs shared by both SFs. However, not all motifs are present in each family. Sequence conservation in the characteristic motifs is high within each family. The highest level of sequence conservation across both SFs is seen in the residues that coordinate binding and hydrolysis of the triphosphate (motifs I, II, and VI). These residues are located in the cleft between the two conserved RecA-like helicase domains [1,2].

The UPF1-like family is formed of a group of enzymes belonging to the SF1-B-5'-3' helicases. UPF1-like helicases show a large functional diversity, with members involved in a variety of RNA regulation pathways. Among them one finds [2]:

• Upf1 (Up-frameshift 1) is a multifunctional RNA and DNA helicase. It is implicated in telomere maintenance and telomerase activity regulation and various mRNA decay pathways [2,3].
• IGHMBP2 (immunoglobulin helicase mu-binding protein 2), a helicase related to mRNA translation and responsible for distal spinal muscular atrophy with respiratory distress type 1 [4].
• SetX/Sen1 (Senataxin), which is involved in transcription termination, R- loop resolving and is linked to amyotrophic lateral sclerosis [5].
• MOV10 (Moloney leukemia virus 10), which is involved in miRNA-dependent regulation [6,7].
• MOV10L1 (Mov10 like 1), also known as CHAMP (cardiac helicase activated by MEF2 protein), with high homology to MOV10, exhibits a restricted germ cell-specific expression patterns and emerges as a conserved key regulator of Piwi-Interacting Rna (piRNA) biogenesis [6].
• Aquarius (also known as intron-binding protein 160, IBP160) is the only spliceosomal helicase belonging to the SF1 superfamily of RNA helicases, whereas all others belong to SF2. It binds precursor-mRNA introns at a defined position [8].
• ZNFX1, a non-canonical E3 ubiquitin ligase stimulated by long ssNAs that regulates the immune response while protecting against RNA viruses [9].

Members of UPF1-like helicases present a common helicase domain organization with two RecA-like subdomains (1A and 2A) containing the classical helicase motifs involved in nucleic acid binding and ATP hydrolysis and two subdomains that modulate RNA binding (1B and 1C) protruding from the first RecA subdomain 1A. Except for the two RecA subdomains, the sequence conservation is very poor. The two RecA subdomains are positioned side by side, separated by a cleft. The ATP nucleotide binds at the bottom of the cleft and interacts directly with the RecA1 subdomain. Subdomains 1A and 2A share the α-β fold with a central seven-stranded parallel β-sheet surounded by α helices, resembling the RecA-like fold seen in all SF1 and SF2 helicases. The canonical motifs I, II, III, V and VI known from other SF1 helicases to be involved in ATP binding and motifs III and Va known to coordinate between NTP and nucleic acid-binding sites are present in the 1A and 2A subdomains (see <PDB:4B3F>) [1,2,3,4,5,6,7,8,9].

The profile we developed covers the two RecA-like subdomains of the UPF1-type helicase core domain.