Molecular basis for the recognition of the human AAUAAA polyadenylation signal

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1419-E1428. doi: 10.1073/pnas.1718723115. Epub 2017 Dec 5.


Nearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3'-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here, we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30, and an AAUAAA RNA at 3.4-Å resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and preorganizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3'-end formation.

Keywords: RNA recognition; WD40 domains; polyadenylation; pre-mRNA 3′-end processing; zinc finger.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cleavage And Polyadenylation Specificity Factor / chemistry
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Poly A / chemistry
  • Poly A / metabolism*
  • Polyadenylation*
  • Protein Conformation
  • RNA Precursors / chemistry
  • RNA Precursors / metabolism*
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*


  • Cleavage And Polyadenylation Specificity Factor
  • Nuclear Proteins
  • RNA Precursors
  • RNA, Messenger
  • WDR33 protein, human
  • Poly A

Associated data

  • PDB/6BLL
  • PDB/6BLY
  • PDB/6BM0