2. Academic Validation
  3. Structure and regulation of ZCCHC4 in m6A-methylation of 28S rRNA

Structure and regulation of ZCCHC4 in m6A-methylation of 28S rRNA

  • Nat Commun. 2019 Nov 6;10(1):5042. doi: 10.1038/s41467-019-12923-x.
Wendan Ren 1,  Jiuwei Lu 1,  Mengjiang Huang 1,  Linfeng Gao 2,  Dongxu Li 3 4,  Gang Greg Wang 3 4,  Jikui Song 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of California, Riverside, CA, 92521, USA.
  • 2 Environmental Toxicology Graduate Program, University of California, Riverside, CA, 92521, USA.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.
  • 4 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 Department of Biochemistry, University of California, Riverside, CA, 92521, USA. [email protected].
  • 6 Environmental Toxicology Graduate Program, University of California, Riverside, CA, 92521, USA. [email protected].
PMID: 31695039 DOI: 10.1038/s41467-019-12923-x
Abstract

N6-methyladenosine (m6A) modification provides an important epitranscriptomic mechanism that critically regulates RNA metabolism and function. However, how m6A writers attain substrate specificities remains unclear. We report the 3.1 Å-resolution crystal structure of human CCHC zinc finger-containing protein ZCCHC4, a 28S rRNA-specific m6A methyltransferase, bound to S-adenosyl-L-homocysteine. The methyltransferase (MTase) domain of ZCCHC4 is packed against N-terminal GRF-type and C2H2 zinc finger domains and a C-terminal CCHC domain, creating an integrated RNA-binding surface. Strikingly, the MTase domain adopts an autoinhibitory conformation, with a self-occluded catalytic site and a fully-closed cofactor pocket. Mutational and enzymatic analyses further substantiate the molecular basis for ZCCHC4-RNA recognition and a role of the stem-loop structure within substrate in governing the substrate specificity. Overall, this study unveils unique structural and enzymatic characteristics of ZCCHC4, distinctive from what was seen with the METTL family of m6A writers, providing the mechanistic basis for ZCCHC4 modulation of m6A RNA methylation.

Figures