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Enzymatic Mechanism and Product Specificity of SET-Domain Protein Lysine Methyltransferases

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Enzymatic Mechanism and Product Specificity of SET-Domain Protein Lysine Methyltransferases Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases Xiaodong Zhang and Thomas C. Bruice† Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106 Contributed by Thomas C. Bruice, February 26, 2008 (sent for review February 12, 2008) Molecular dynamics and hybrid quantum mechanics/molecular mechanics have been used to investigate the mechanisms of ؉ AdoMet methylation of protein-Lys-NH2 catalyzed by the lysine methyltransferase enzymes: histone lysine monomethyltrans- ferase SET7/9, Rubisco large-subunit dimethyltransferase, viral histone lysine trimethyltransferase, and the Tyr245Phe mutation of SET7/9. At neutrality in aqueous solution, primary amines are .؉ ؉ Scheme 1 protonated. The enzyme reacts with Lys-NH3 and AdoMet spe- ؉ ؉ cies to provide an Enz⅐Lys-NH3 ⅐ AdoMet complex. The close ؉ positioning of two positive charges lowers the pKa of the Lys-NH3 water molecule at the active site of SET-domain PKMTs entity, a water channel appears, and the proton escapes to the functions as the proton acceptor. However, H Oϩ is a much ⅐ ⅐؉ 3 3 aqueous solvent; then the reaction Enz Lys-NH2 AdoMet stronger acid than Lys-CH -NH ϩ, so that this water by itself ⅐ ؉⅐ 2 3 Enz Lys-N(Me)H2 AdoHcy occurs. Repeat of the sequence provides could not deprotonate the charged substrate. Guo et al. (21) dimethylated lysine, and another repeat yields a trimethylated suggested that the conserved Tyr-335, as a phenolate, in lysine. The sequence is halted at monomethylation when the ؉ ؉ SET7/9 acts as a base for the deprotonation. This proposal is conformation of the Enz⅐Lys-N(Me)H2 ⅐ AdoMet has the methyl unlikely because Tyr-335-OH has a calculated pKa of positioned to block formation of a water channel. The sequence of Ͼ13.0 (22). ⅐ reactions stops at dimethylation if the conformation of Enz Lys- Related are proposed mechanisms to explain the origin of ؉⅐؉ N(Me)2H AdoMet has a methyl in position, which forbids the product specificity by PKMTs. Hu et al. (23) proposed, on the formation of the water channel. basis of their molecular dynamics (MD) simulations, that the distributions of near-attack conformation at the ground state ͉ ͉ molecular dynamics QM/MM SCCDFTB determined the product specificity by PKMTs. Xiao et al. (9) proposed that the mutation of Tyr-245 into Phe or Ala in SET7/9 he packaged structure of DNA in eukaryotic cells is called alters the product specificity, and Cheng et al. (24) proposed that Tchromatin. Chromatin activity is mainly controlled by site- the Tyr/Phe switch controls the product by PKMTs based on specific lysine methylation catalyzed by protein lysine methyl- their mutation experiments. However, these important experi- transferase enzymes (PKMT) (1). Absence of the methylation at mental and computational results do not deal with the crucial the site-specific lysine by a PKMT is the origin of a number of questions: How do the charged substrates deprotonate, and what human diseases, notably cancer (2). controls the specificity? All but one (3, 4) of the known PKMTs have a SET-domain We report here the mechanisms of the catalysis by three structure (5, 6). These PKMTs include human histone methyl- SET-domain enzymes: histone lysine monomethyltransferase transferase SET7/9 (7–11), human SET8 (also known as PR- SET7/9 as well as its Tyr245Phe mutation, Rubisco LSMT, and SET7) (12, 13), Neurospora DIM-5 (14), histone lysine methyl- vSET. Finally, a definitive mechanism is provided. The details of transferase Clr4 (15), viral histone lysine methyltransferase computations used were described in previous reports (22, (vSET) (16, 17), and plant Rubisco large-subunit methyltrans- 29, 30). ferase (LSMT) (18, 19). A SET domain, originally identified in three Drosophila genes involved in epigenetic processes, contains Results and Discussions Ϸ130 aa residues. The cofactor S-adenosylmethionine Processivity and Multiplicity of the Methyl Transfer Reactions. His- ϩ ( AdoMet) and substrate bind at two adjacent sites of the tone lysine methyltransferase SET7/9 only catalyzes the transfer ϩ conserved SET domain. The AdoMet methyl group approaches of one methyl group to the target lysine (Lys-4). LSMT transfers the target lysine amino group through a channel that passes two methyl groups to a single lysine (Lys). vSET catalyzes the through the middle of this SET domain to form Enz⅐Lys- triple methylation of the target lysine Lys-27 (Scheme 1). There ϩ⅐ϩ ϩ NH3 AdoMet. are three reaction steps in the AdoMet methylation of lysine- PKMT enzymes transfer one, two, or three methyl groups to NH2 catalyzed by a methyltransferase: (i) combination of en- ϩ ϩ target lysine residues depending on the particular enzyme. zyme with Lys-NH3 and AdoMet, (ii) proton dissociation to ϩ This is called product specificity (shown in Scheme 1). For provide Enz⅐Lys-NH2⅐ AdoMet, and (iii) methyl transfer pro- ϩ example, LSMT transfers two methyl groups to a single lysine viding Enz⅐Lys-N(Me)H2 ⅐AdoHcy and the release of AdoHcy. (Lys), so that we refer to LSMT as a dimethyltranferase in the ؉ present study. Only a neutral Lys-NH2, Lys-N(Me)H, or pKa Calculation of Lys-4-NH3 and Tyr-335-OH in SET7/9. The pKasof ϩ ϩ Lys-N(Me)2 can be methylated by the AdoMet cofactor. Lys-4-NH and Tyr-335-OH are listed in Table 1. The calcu- ϩ ϩ ϩ 3 Lys-NH3 , Lys-N(Me)H2 , or Lys-N(Me)2H must be depro- tonated before methylation (Scheme 1). Xiao et al. (13) proposed that the bulk solvent might play an important role in Author contributions: X.Z. and T.C.B. designed research; X.Z. performed research; X.Z. the dissociation of the proton of the positively charged lysine. analyzed data; and X.Z. and T.C.B. wrote the paper. Because the active site fits tightly to the reactants and does not The authors declare no conflict of interest. allow the entrance of solvent molecules, this proposal is †To whom correspondence should be addressed. E-mail: [email protected]. incomplete and insufficient. Dirk et al. (20) suggested that a © 2008 by The National Academy of Sciences of the USA 5728–5732 ͉ PNAS ͉ April 15, 2008 ͉ vol. 105 ͉ no. 15 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0801788105 Downloaded by guest on September 29, 2021 3 Table 1. The calculated pKa values of the target lysine Lys4 and Table 2. The average density (in atoms per Å ) of the water the conversed tyrosine Tyr335 in the various complexes of the molecules at the positions of the water channel (shown SET7/9 monomethyltransferase in Figs. 1 and 5) during the MD simulations on ؉ ؉ complex SET7/9⅐Lys4-NH3 ⅐ AdoMet and pKa ؉ ؉ SET7/9[Y245F]⅐Lys4-N(Me)H2 ⅐ AdoMet Complex Lys4-NH ϩ Tyr335-OH 3 Complex Position Density ϩ SET7/9⅐Lys4-NH3 10.9 Ϯ 0.4 14.3 Ϯ 3.0 ϩ ϩ SET7/9⅐Lys4-NH3 ⅐ AdoMet (Fig. 1) Wat559 0.006 SET7/9 Lys4-NH ϩ⅐ϩAdoMet 8.2 Ϯ 0.6 16.6 Ϯ 4.2 3 A 0.009 SET7/9 Lys4-N(Me)H ϩ⅐ϩAdoMet 14.7 Ϯ 4.9 13.7 Ϯ 2.4 2 B 0.011 The pKa is calculated by solving the Poisson–Bolztmann equation imple- C 0.017 mented in the PBEQ module of CHARMM suite at the MM level, with 80.0 and D 0.019 4.0 as the dielectric constants of water and protein, respectively. E 0.022 F 0.026 G 0.028 lated pKa of the conserved Tyr-335-OH eliminates the presence H 0.027 Ϫ ⅐ of Tyr-335-O as the base to deprotonate Enz Lys-4- I 0.024 ϩ⅐ϩ ⅐ ϩ⅐ϩ NH3 AdoMet or Enz Lys-4-N(Me)H2 AdoMet. The calcu- Mutated SET7/9[Y245F]⅐Lys4- ϩ ⅐ lated pKa of Lys-4-NH3 in complex SET7/9 Lys-4- N(Me)H ϩ⅐ϩAdoMet (Fig. 5) Wat565 0.007 ϩ⅐ϩ Ϯ 2 NH3 AdoMet is 8.2 0.6. The decrease in pKa from 10.9 to Wat660 0.007 ϩ 8.2 on AdoMet addition is due to the electrostatic interaction Wat559 0.001 ϩ ϩ of the closely positively charged Lys-4-NH3 and AdoMet A 0.014 species. Proton dissociation creates the reactive complex SET7/ B 0.017 ϩ 9⅐Lys-4-NH2⅐ AdoMet. How does the proton dissociate from the C 0.020 active site? D 0.015 E 0.026 MD Simulations on Enzyme Michaelis Complexes. Inspections of the F 0.028 MD trajectories of the various enzyme complexes establish G 0.028 that a water channel for proton escape is formed only upon the H 0.021 establishment of the ϩAdoMet complexes: SET7/9⅐Lys-4- ϩ ϩ ϩ ϩ The solvent water molecules are designated by A–I, and I is on the surface NH3 ⅐ AdoMet, LSMT⅐Lys-NH3 ⅐ AdoMet, LSMT⅐Lys- ϩ ϩ ϩ ϩ of the water sphere with a 25-Å radius. The crystal water molecules are N(Me)H2 ⅐ AdoMet, vSET⅐Lys-27-NH3 ⅐ AdoMet, ⅐ ϩ⅐ϩ ⅐ designated by Wat. The density values mean how many water molecules fill vSET Lys-27-N(Me)H2 AdoMet, and vSET Lys-27- the given position during the molecular dynamics simulations. Nonzero values ϩ ϩ N(Me)2H ⅐ AdoMet. The presence of a water channel is are expected to indicate that this position is filled by the water molecule. established by determining the distances between the hydro- gen and oxygen atoms of the continuous chain of water molecules. A distance of 1.85 Å supports a water channel.
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