5ytx | pdb_00005ytx
Crystal structure of YB1 cold-shock domain in complex with UCAACU
Structural highlights
Function[YBOX1_HUMAN] Mediates pre-mRNA alternative splicing regulation. Binds to splice sites in pre-mRNA and regulates splice site selection. Binds and stabilizes cytoplasmic mRNA. Contributes to the regulation of translation by modulating the interaction between the mRNA and eukaryotic initiation factors (By similarity). Regulates the transcription of numerous genes. Its transcriptional activity on the multidrug resistance gene MDR1 is enhanced in presence of the APEX1 acetylated form at 'Lys-6' and 'Lys-7'. Binds to promoters that contain a Y-box (5'-CTGATTGGCCAA-3'), such as MDR1 and HLA class II genes. Promotes separation of DNA strands that contain mismatches or are modified by cisplatin. Has endonucleolytic activity and can introduce nicks or breaks into double-stranded DNA (in vitro). May play a role in DNA repair. Component of the CRD-mediated complex that promotes MYC mRNA stability. Binds preferentially to the 5'-[CU]CUGCG-3' motif in vitro.[1] [2] [3] [4] [5] [6] [7] [8] The secreted form acts as an extracellular mitogen and stimulates cell migration and proliferation. Publication Abstract from PubMedThe Y-box binding protein 1 (YB-1) is a member of the cold shock domain (CSD) protein family and is recognized as an oncogenic factor in several solid tumors. By binding to RNA, YB-1 participates in several steps of posttranscriptional regulation of gene expression, including mRNA splicing, stability, and translation; microRNA (miRNA) processing; and stress granule assembly. However, the mechanisms in YB-1-mediated regulation of RNAs are unclear. Previously, we used both systematic evolution of ligands by exponential enrichment (SELEX) and individual-nucleotide resolution UV crosslinking and immunoprecipitation coupled RNA-seq (iCLIP-seq) analyses, which defined the RNA-binding consensus sequence of YB-1 as CA(U/C)C. We also reported that through binding to its core motif CAUC in primary transcripts, YB-1 regulates the alternative splicing of a CD44 variable exon and the biogenesis of miR-29b-2 during both Drosha and Dicer steps. To elucidate the molecular basis of the YB-1-RNA interactions, we report high-resolution crystal structures of the YB-1 CSD in complex with different RNA oligos at 1.7 A resolution. The structure revealed that CSD interacts with RNA mainly through pi-pi stacking interactions assembled by four highly conserved aromatic residues. Interestingly, YB-1 CSD forms a homodimer in solution, and we observed that two residues, Tyr-99 and Asp-105, at the dimer interface are important for YB-1 CSD dimerization. Substituting these two residues with Ala reduced CSD's RNA binding activity and abrogated the splicing activation of YB-1 targets. The YB-1 CSD-RNA structures presented here at atomic resolution provide mechanistic insights into gene expression regulated by CSD-containing proteins. Crystal structure of a Y-box binding protein 1 (YB-1)-RNA complex reveals key features and residues interacting with RNA.,Yang XJ, Zhu H, Mu SR, Wei WJ, Yuan X, Wang M, Liu Y, Hui J, Huang Y J Biol Chem. 2019 Jun 3. pii: RA119.007545. doi: 10.1074/jbc.RA119.007545. PMID:31160337[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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