LIG_ULM_U2AF65_1

An unusal subgroup of RRM domains (PF00076) termed UHMs (U2AF Homology Motifs) have been found to have no (or weak) RNA-binding activity (Kielkopf,2004). Instead of RNA, UHMs appear to bind to short induced fit protein elements. The known UHM Ligand Motifs (ULMs) show a typical signature of a short positively charged run preceding a Trp-Asp pair (although the Asp is not always conserved.) ULM sequences with important functions in mRNA processing were found in the constitutive splicing factors U2AF65, SF1 and SAP155. The structure of the U2AF65-ULM reveals a larger induced fit module than the signature motif (1JMT) (Kielkopf,2001). It is recognized by the UHM in U2AF35 with low nanomolar affinity and mediates the heterodimerization of these two proteins, which is crucial for U2 snRNP recruitment in early splicing initiation. The SF1 ULM is used for recruitment to the branch point sequence by binding to the U2AF65-UHM (Selenko,2003). ATP-dependent rearrangements of the snRNPs cause the SF1-ULM to be replaced by ULMs in SAP155 later in the splicing process (Thickman,2006). Thus, the UHM-ULM interactions known so far all mediate essential interactions in the splicing process.

The Rev proteins of HIV1, HIV2 and SIV have a highly conserved ULM mimic (Pabis,2019). The main cellular UHM-containing protein that binds to Rev is U2AF65. As well as being a constitutive splicing protein, U2AF65 is also involved in nuclear export of mRNAs. The ULM is directly involved in inhibition of splicing by Rev, switching on the late HIV gene expression which requires unspliced HIV mRNA.