7UK1

Complex Structure of Human Polypyrimidine Splicing Factor (PSF/SFPQ) with Murine Virus-like 30S Transcript-1 (VS30-1) Reveals Cooperative Binding of RNA

Summary for 7UK1

• Entry DOI: 10.2210/pdb7uk1/pdb
• Descriptor: Splicing factor, proline- and glutamine-rich, MAGNESIUM ION (3 entities in total)
• Functional Keywords: polypyridimine-binding splicing factor, 5'-polyuridine negative-sense (5'-pun) template, rna-dependent dna-binding regulation, dna-binding domain (dbd), rna-binding motif (rrm), vl30-1, allostery, cooperativity, splicing
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 95650.89

Authors

Lomakin, I.B.,Wang, J. (deposition date: 2022-03-31, release date: 2022-09-21, Last modification date: 2023-10-18)

Primary citation

Wang, J.,Sachpatzidis, A.,Christian, T.D.,Lomakin, I.B.,Garen, A.,Konigsberg, W.H.
Insight into the Tumor Suppression Mechanism from the Structure of Human Polypyrimidine Splicing Factor (PSF/SFPQ) Complexed with a 30mer RNA from Murine Virus-like 30S Transcript-1.
Biochemistry, 61:1723-1734, 2022

PubMed Abstract: Human polypyrimidine-binding splicing factor (PSF/SFPQ) is a tumor suppressor protein that regulates the gene expression of several proto-oncogenes and binds to the 5'-polyuridine negative-sense template (5'-PUN) of some RNA viruses. The activity of PSF is negatively regulated by long-noncoding RNAs, human metastasis associated in lung adenocarcinoma transcript-1 and murine virus-like 30S transcript-1 (VL30-1). PSF is a 707-amino acid protein that has a DNA-binding domain and two RNA recognition motifs (RRMs). Although the structure of the apo-truncated PSF is known, how PSF recognizes RNA remains elusive. Here, we report the 2.8 Å and 3.5 Å resolution crystal structures of a biologically active truncated construct of PSF (sPSF, consisting of residues 214-598) alone and in a complex with a 30mer fragment of VL30-1 RNA, respectively. The structure of the complex reveals how the 30mer RNA is recognized at two U-specific induced-fit binding pockets, located at the previously unrecognized domain-swapped, inter-subunit RRM1 (of the first subunit)-RRM2 (of the second subunit) interfaces that do not exist in the apo structure. Thus, the sPSF dimer appears to have two conformations in solution: one in a low-affinity state for RNA binding, as seen in the apo-structure, and the other in a high-affinity state for RNA binding, as seen in the sPSF-RNA complex. PSF undergoes an all or nothing transition between having two or no RNA-binding pockets. We predict that the RNA binds with a high degree of positive cooperativity. These structures provide an insight into a new regulatory mechanism that is likely involved in promoting malignancies and other human diseases.

PubMed: 35998361
DOI: 10.1021/acs.biochem.2c00192

Experimental method

X-RAY DIFFRACTION (2.7 Å)