Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT

Raymond C. Trievel; E. Megan Flynn; Robert L. Houtz; James H. Hurley

doi:10.1038/nsb946

Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT

Raymond C. Trievel, E. Megan Flynn, Robert L. Houtz, James H. Hurley

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Abstract

SET domain protein methyltransferases catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine (AdoMet) to specific lysine residues of protein substrates, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex. The crystal structures of pea Rubisco large subunit methyltransferase (LSMT) in ternary complexes with either lysine or ε-N-methyllysine (MeLys) and the product S-adenosylhomocysteine (AdoHcy) were determined to resolutions of 2.65 and 2.55 Å, respectively. The ζ-methyl group of MeLys is bound to the enzyme via carbon-oxygen hydrogen bonds that play a key role in catalysis. The methyl donor and acceptor are aligned in a linear geometry for S_N2 nucleophilic transfer of the methyl group during catalysis. Differences in hydrogen bonding between the MeLys ε-amino group and Rubisco LSMT and SET7/9 explain why Rubisco LSMT generates multiply methylated Lys, wheras SET7/9 generates only MeLys.

Original language	English
Pages (from-to)	545-552
Number of pages	8
Journal	Nature Structural Biology
Volume	10
Issue number	7
DOIs	https://doi.org/10.1038/nsb946
State	Published - Jul 1 2003

Bibliographical note

Funding Information:
We would like to thank S. Gamblin for SET7/9–AdoHcy–histone H3 ternary complex coordinates, and D. Engelman and G. Felsenfeld for insightful discussions. Research by R.L.H. and E.M.F. was supported by the DOE, Division of Energy Biosciences.

Funding

We would like to thank S. Gamblin for SET7/9–AdoHcy–histone H3 ternary complex coordinates, and D. Engelman and G. Felsenfeld for insightful discussions. Research by R.L.H. and E.M.F. was supported by the DOE, Division of Energy Biosciences.

Funders	Funder number
Division of Energy Biosciences
U.S. Department of Energy Oak Ridge National Laboratory U.S. Department of Energy National Science Foundation National Energy Research Scientific Computing Center
National Institute of Diabetes and Digestive and Kidney Diseases	Z01DK036118
National Institute of Diabetes and Digestive and Kidney Diseases

ASJC Scopus subject areas

Structural Biology
Biochemistry
Genetics

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title = "Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT",

abstract = "SET domain protein methyltransferases catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine (AdoMet) to specific lysine residues of protein substrates, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex. The crystal structures of pea Rubisco large subunit methyltransferase (LSMT) in ternary complexes with either lysine or ε-N-methyllysine (MeLys) and the product S-adenosylhomocysteine (AdoHcy) were determined to resolutions of 2.65 and 2.55 {\AA}, respectively. The ζ-methyl group of MeLys is bound to the enzyme via carbon-oxygen hydrogen bonds that play a key role in catalysis. The methyl donor and acceptor are aligned in a linear geometry for SN2 nucleophilic transfer of the methyl group during catalysis. Differences in hydrogen bonding between the MeLys ε-amino group and Rubisco LSMT and SET7/9 explain why Rubisco LSMT generates multiply methylated Lys, wheras SET7/9 generates only MeLys.",

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note = "Funding Information: We would like to thank S. Gamblin for SET7/9–AdoHcy–histone H3 ternary complex coordinates, and D. Engelman and G. Felsenfeld for insightful discussions. Research by R.L.H. and E.M.F. was supported by the DOE, Division of Energy Biosciences.",

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AU - Trievel, Raymond C.

AU - Flynn, E. Megan

AU - Houtz, Robert L.

AU - Hurley, James H.

N1 - Funding Information: We would like to thank S. Gamblin for SET7/9–AdoHcy–histone H3 ternary complex coordinates, and D. Engelman and G. Felsenfeld for insightful discussions. Research by R.L.H. and E.M.F. was supported by the DOE, Division of Energy Biosciences.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - SET domain protein methyltransferases catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine (AdoMet) to specific lysine residues of protein substrates, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex. The crystal structures of pea Rubisco large subunit methyltransferase (LSMT) in ternary complexes with either lysine or ε-N-methyllysine (MeLys) and the product S-adenosylhomocysteine (AdoHcy) were determined to resolutions of 2.65 and 2.55 Å, respectively. The ζ-methyl group of MeLys is bound to the enzyme via carbon-oxygen hydrogen bonds that play a key role in catalysis. The methyl donor and acceptor are aligned in a linear geometry for SN2 nucleophilic transfer of the methyl group during catalysis. Differences in hydrogen bonding between the MeLys ε-amino group and Rubisco LSMT and SET7/9 explain why Rubisco LSMT generates multiply methylated Lys, wheras SET7/9 generates only MeLys.

AB - SET domain protein methyltransferases catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine (AdoMet) to specific lysine residues of protein substrates, such as the N-terminal tails of histones H3 and H4 and the large subunit of the Rubisco holoenzyme complex. The crystal structures of pea Rubisco large subunit methyltransferase (LSMT) in ternary complexes with either lysine or ε-N-methyllysine (MeLys) and the product S-adenosylhomocysteine (AdoHcy) were determined to resolutions of 2.65 and 2.55 Å, respectively. The ζ-methyl group of MeLys is bound to the enzyme via carbon-oxygen hydrogen bonds that play a key role in catalysis. The methyl donor and acceptor are aligned in a linear geometry for SN2 nucleophilic transfer of the methyl group during catalysis. Differences in hydrogen bonding between the MeLys ε-amino group and Rubisco LSMT and SET7/9 explain why Rubisco LSMT generates multiply methylated Lys, wheras SET7/9 generates only MeLys.

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Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT

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