Structure and catalytic mechanism of a SET domain protein methyltransferase

Cell. 2002 Oct 4;111(1):91-103. doi: 10.1016/s0092-8674(02)01000-0.

Abstract

Protein lysine methylation by SET domain enzymes regulates chromatin structure, gene silencing, transcriptional activation, plant metabolism, and other processes. The 2.6 A resolution structure of Rubisco large subunit methyltransferase in a pseudo-bisubstrate complex with S-adenosylhomocysteine and a HEPES ion reveals an all-beta architecture for the SET domain embedded within a larger alpha-helical enzyme fold. Conserved regions of the SET domain bind S-adenosylmethionine and substrate lysine at two sites connected by a pore. We propose that methyl transfer is catalyzed by a conserved Tyr at a narrow pore connecting the sites. The cofactor enters by a "back door" on the opposite side of the enzyme from substrate, promoting highly specific protein recognition and allowing addition of multiple methyl groups.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Chromatin / chemistry
  • Conserved Sequence
  • DNA Mutational Analysis
  • DNA-Binding Proteins / chemistry*
  • Dimerization
  • Dose-Response Relationship, Drug
  • Drosophila Proteins / chemistry*
  • Electrons
  • Gene Silencing
  • HEPES / pharmacology
  • Histones / chemistry
  • Kinetics
  • Ligands
  • Lysine / chemistry
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry*
  • Peas / enzymology
  • Polycomb Repressive Complex 2
  • Protein Binding
  • Protein Methyltransferases / chemistry*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Repressor Proteins / chemistry*
  • Spinacia oleracea / enzymology
  • Substrate Specificity
  • Transcription Factors*
  • Transcriptional Activation
  • Tyrosine / chemistry

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Histones
  • Ligands
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors
  • Trl protein, Drosophila
  • Tyrosine
  • Protein Methyltransferases
  • E(z) protein, Drosophila
  • Polycomb Repressive Complex 2
  • Lysine
  • HEPES