5SYB

Crystal structure of human PHF5A

Summary for 5SYB

• Entry DOI: 10.2210/pdb5syb/pdb
• Descriptor: PHD finger-like domain-containing protein 5A, ZINC ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: core component, sf3b complex, human spliceosome, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q7RTV0
• Total number of polymer chains: 2
• Total formula weight: 25968.15

Authors

Tsai, J.H.C.,Teng, T.,Zhu, P.,Fekkes, P.,Larsen, N.A. (deposition date: 2016-08-10, release date: 2016-09-07, Last modification date: 2024-03-06)

Primary citation

Teng, T.,Tsai, J.H.,Puyang, X.,Seiler, M.,Peng, S.,Prajapati, S.,Aird, D.,Buonamici, S.,Caleb, B.,Chan, B.,Corson, L.,Feala, J.,Fekkes, P.,Gerard, B.,Karr, C.,Korpal, M.,Liu, X.,T Lowe, J.,Mizui, Y.,Palacino, J.,Park, E.,Smith, P.G.,Subramanian, V.,Wu, Z.J.,Zou, J.,Yu, L.,Chicas, A.,Warmuth, M.,Larsen, N.,Zhu, P.
Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex.
Nat Commun, 8:15522-15522, 2017

PubMed Abstract: Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons. We determine the crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface. Analysis of the cryo-EM spliceosome B complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these splicing modulators.

PubMed: 28541300
DOI: 10.1038/ncomms15522

Experimental method

X-RAY DIFFRACTION (1.82 Å)