2YH0

Solution structure of the closed conformation of human U2AF65 tandem RRM1 and RRM2 domains

Summary for 2YH0

• Entry DOI: 10.2210/pdb2yh0/pdb
• Related: 1JMT 1O0P 1OPI 1U2F 2G4B 2U2F 2YH1 2YH4
• NMR Information: BMRB: 17622
• Descriptor: SPLICING FACTOR U2AF 65 KDA SUBUNIT (1 entity in total)
• Functional Keywords: pre-mrna splicing, transcription, rna binding protein, mrna processing
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 21510.53

Authors

Mackereth, C.D.,Madl, T.,Simon, B.,Zanier, K.,Gasch, A.,Sattler, M. (deposition date: 2011-04-26, release date: 2011-07-20, Last modification date: 2024-05-15)

Primary citation

Mackereth, C.D.,Madl, T.,Bonnal, S.,Simon, B.,Zanier, K.,Gasch, A.,Rybin, V.,Valcarcel, J.,Sattler, M.
Multi-Domain Conformational Selection Underlies Pre-Mrna Splicing Regulation by U2Af
Nature, 475:408-, 2011

PubMed Abstract: Many cellular functions involve multi-domain proteins, which are composed of structurally independent modules connected by flexible linkers. Although it is often well understood how a given domain recognizes a cognate oligonucleotide or peptide motif, the dynamic interaction of multiple domains in the recognition of these ligands remains to be characterized. Here we have studied the molecular mechanisms of the recognition of the 3'-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65) as a key early step in pre-mRNA splicing. We show that the tandem RNA recognition motif domains of U2AF65 adopt two remarkably distinct domain arrangements in the absence or presence of a strong (that is, high affinity) polypyrimidine tract. Recognition of sequence variations in the polypyrimidine tract RNA involves a population shift between these closed and open conformations. The equilibrium between the two conformations functions as a molecular rheostat that quantitatively correlates the natural variations in polypyrimidine tract nucleotide composition, length and functional strength to the efficiency to recruit U2 snRNP to the intron during spliceosome assembly. Mutations that shift the conformational equilibrium without directly affecting RNA binding modulate splicing activity accordingly. Similar mechanisms of cooperative multi-domain conformational selection may operate more generally in the recognition of degenerate nucleotide or amino acid motifs by multi-domain proteins.

PubMed: 21753750
DOI: 10.1038/NATURE10171

Experimental method

SOLUTION NMR