6UCA

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

(2019) Nat Commun 10: 5042-5042

• PubMed: 31695039 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41467-019-12923-x
• Primary Citation of Related Structures:  
  6UCA


• PubMed Abstract: 
  

  N ⁶ -methyladenosine (m ⁶ A) modification provides an important epitranscriptomic mechanism that critically regulates RNA metabolism and function. However, how m ⁶ A 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 m ⁶ A 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 m ⁶ A writers, providing the mechanistic basis for ZCCHC4 modulation of m ⁶ A RNA methylation.

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Organizational Affiliation: 

Department of Biochemistry, University of California, Riverside, CA, 92521, USA.