Structure and catalytic mechanism of a SET domain protein methyltransferase

Raymond C. Trievel, Bridgette M. Beach, Lynnette M.A. Dirk, Robert L. Houtz, James H. Hurley

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

Protein lysine methylation by SET domain enzymes regulates chromatin structure, gene silencing, transcriptional activation, plant metabolism, and other processes. The 2.6 Å resolution structure of Rubisco large subunit methyltransferase in a pseudo-bisubstrate complex with S-adenosylhomocysteine and a HEPES ion reveals an all-β architecture for the SET domain embedded within a larger α-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.

Original languageEnglish
Pages (from-to)91-103
Number of pages13
JournalCell
Volume111
Issue number1
DOIs
StatePublished - Oct 4 2002

Bibliographical note

Funding Information:
We thank G. Felsenfeld, F. Dyda, and M. Litt for discussions, S. Misra for assistance preparing figures, R. Ghirlando for analytical ultracentrifugation, and S. Misra, B. Canagarajah, and G. Miller for synchrotron data collection. We acknowledge use of beamlines 19-ID, APS, Argonne, IL; 5.0.2, ALS, Berkeley, CA; and A1, CHESS, Cornell Univ., Ithaca, NY. R.L.H. was supported by the DOE, Division of Energy Biosciences (grant DE-FG02-92ER20075).

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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