Abstract
The mixed lineage leukaemia (MLL) family of proteins (including MLL1–MLL4, SET1A and SET1B) specifically methylate histone 3 Lys4, and have pivotal roles in the transcriptional regulation of genes involved in haematopoiesis and development. The methyltransferase activity of MLL1, by itself severely compromised, is stimulated by the three conserved factors WDR5, RBBP5 and ASH2L, which are shared by all MLL family complexes. However, the molecular mechanism of how these factors regulate the activity of MLL proteins still remains poorly understood. Here we show that a minimized human RBBP5–ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases. Our structural, biochemical and computational analyses reveal a two-step activation mechanism of MLL family proteins. These findings provide unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggest a universal regulation mechanism for most histone methyltransferases.
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–RBBP5AS-ABM–ASH2LSPRY).References
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Acknowledgements
We thank staffs of beamlines BL18U, BL19U1 and 17U at the National Center for Protein Sciences Shanghai and Shanghai Synchrotron Radiation Facility for their assistance in data collection. We are grateful to protein expression, protein purification and mass spectrometry facilities at the National Center for Protein Sciences Shanghai for their instrument support and technical assistance. This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08010201 to M.L. and Y.C., XDB08030302 to C.T.), the Ministry of Science and Technology of China (2013CB910402 to M.L., 2013CB910401 to Y.C., 2012AA01A305 and 2012CB721002 to G.L., 2011CB910400 to C.T.), the National Science and Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ of China (2014ZX09507002-005 to M.L.), the National Natural Science Foundation of China (31330040 to M.L., 31470737 to Y.C. ,and 91430110 to G.L.), the Basic Research Project of Shanghai Science and Technology Commission (14JC1407200 to Y.C.), the National Institutes of Health (R01 GM082856 to Y.D.), and Fundamental Research for the Central University (WK2340000064 to C.T.). Y.C. is a recipient of the Thousand Young Talents Program of the Chinese government.
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Contributions
M.L. and Y.C. conceived and supervised the project. M.L. and Y.D. initiated the project. Y.L., J.H., C.H. and Y.C. purified the proteins, performed crystallization and determined the crystal structure. Y.L., J.H., F.C., C.H., J.W., Y.W. and Y.C. performed the biochemical assays. Z.L., P.S. and C.T. performed 19F-NMR experiments. S.L. and J.Z. performed normal mode analysis. Y.Z., L.C. and G.L. performed molecular dynamics and QM/MM simulation. D.L. and Y.D. contributed to manuscript preparation. G.L., Y.C. and M.L. analysed the data and wrote the manuscript.
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Extended data figures and tables
Extended Data Figure 1 Methyltransferase activity of MLL1–MLL4, SET1A and SET1B with the different combinations of WDR5, RBBP5 and ASH2L.
a, HKMT activities determined by the 3H-methyl-incorporation assay. MLL constructs were chosen to contain both the WIN motif and the SET domain. Full-length WDR5, RBBP5 and ASH2L were used. The HKMT activities are normalized to the activity of the MLL–WDR5–RBBP5–ASH2L complexes setting at 100%. Mean ± s.d. (n = 3) are shown. b, Representative MALDI–TOF spectra at different time points for MLL complexes and apo MLL proteins clearly revealed that MLL complexes have much higher HKMT activities than apo MLL proteins. The peaks for unmodified (un) and mono-, di- and tri-methylated products are labelled. The minor peaks are sodium adducts of major peaks (+22 Da). Asterisks denote the adduct of un-peaks; filled circles denote the adduct of mono-peaks; and filled squares denote the adduct of di-peaks. c, Comparison of the overall rates of the methylation reactions catalysed by different MLL proteins in the presence of WDR5–ASH2L–RBBP5 or ASH2L–RBBP5. The overall rates were derived by fitting the decrease in the relative intensity of the unmodified H3 peptide peaks in MALDI–TOF mass spectra using one-phase exponential decay model [Lys4]t = [Lys4]0e−kt.
Extended Data Figure 2 Interactions between MLL proteins and RBBP5–ASH2L.
a, GST pull-down assays showed direct interactions between MLL proteins and RBBP5–ASH2L. ASH2L C-terminal SPRY domain has been previously shown to interact with RBBP5. GST-fused ASH2LSPRY was incubated with full-length RBBP5 and different MLLSET proteins in the GST pull-down assay. Bound proteins were eluted and separated by SDS–PAGE. Three different salt concentration buffers were tested. b, Fluorescence polarization assay shows that MLL proteins can interact with RBBP5AS-ABM–ASH2LSPRY with different affinities. For MLL1, SET1A and SET1B, lower limits of the Kd values are reported because saturation of the binding could not be achieved in fluorescence polarization assays. c, GST–RBBP5 alone cannot pull down MLL proteins in the buffer with 300 mM NaCl. d, GST–ASH2LSPRY alone cannot pull down MLL proteins in the buffer with 300 mM NaCl. e, The RBBP5–ASH2L interaction is highly dependent on the salt concentration used in the assay. ITC measurements were carried out using ASH2LSPRY and RBBP5AS-ABM under buffer conditions with different salt concentrations. f, The requirement of WDR5 in methyltransferase activity of the MLL1 complex is sensitive to protein concentration. MLL1 (5 μM) could be markedly stimulated by equal amounts of ASH2L–RBBP5, and WDR5 had a minor stimulation effect. g, HKMT activities of RBBP5–MLL1 fusion proteins in the presence of ASH2L or ASH2L and WDR5. Full-length RBBP5 was fused to MLL1 (residues 3754–3969) with a GGSGGS linker. The addition of ASH2L substantially stimulated the HKMT activity of the RBBP5–MLL1 fusion protein, while further addition of WDR5 only had a marginal effect.
Extended Data Figure 3 The overall structure of the MLL3SET–RBBP5AS-ABM–ASH2LSPRY–H3 complex.
a, The overall structure of the MLL3SET–RBBP5AS-ABM–ASH2LSPRY–H3 complex in cartoon diagram. ASH2L is in yellow-orange, RBBP5 in cyan, MLL3SET in salmon, the H3 peptide in yellow, and cofactor product (AdoHcy) in blue. The electron density (2Fo − Fc) map, contoured at 1σ, is shown for the RBBP5 fragment, the H3 peptide and AdoHcy. b, The electron density (2Fo − Fc) map, contoured at 1σ, is shown around the substrate-binding channel. There are two complexes in one asymmetric unit. One complex has clear electron density for H3 residues 2–7 (left), while the other exhibits no extra density in the substrate channel (right). c, Cofactor interaction network. Residues important for the AdoHcy–MLL3SET interaction are shown in stick models. Hydrogen bonds are indicated by dashed magenta lines. d, The space-filling model of MLL3SET shows that AdoHcy and H3 bind to the opposite surfaces on MLL3SET. The distance between the sulfur atom and ε-amine of Lys4 is shown. e, The binding interface between MLL3SET and H3. f, MLL3SET is in surface representation and coloured according to its electrostatic potential. Thr3 of H3 sits snugly on a shallow hydrophobic depression, which cannot accommodate residues with a large side chain. Arg2 is involved in electrostatic interactions with MLL3SET. g, Sequence alignment of histone methylation sites. Residues are numbered relative to the target lysine. Because only the Lys4 site of H3 contains a large basic residue and a small residue occupying the −2 and −1 positions respectively, Arg(−2) and Thr(−1) define the substrate specificity of MLL complexes.
Extended Data Figure 4 Sequence alignment of MLL homologues from human, Drosophila and Saccharomyces cerevisiae.
The WDR5-interacting motif (WIN) and SET domain are aligned. Secondary structure assignments based on the MLL3 structure are shown as cylinders (α-helices) and arrows (β-strands) above the sequences. The WIN motif is coloured in blue, SET-N in green, SET-I in orange, SET-C in purple and post-SET in magenta. Conserved residues important for RBBP5–ASH2L interactions are highlighted in magenta. Four Zn-binding cysteine residues are highlighted in pale yellow. Residues important for cofactor binding are in brown; residues important for substrate H3 binding and maintenance of the active centre are in grey. Two glycine residues, which serve as the hinge for SET-I motif rotation, are indicated by blue dots. The residues with the corresponding MLL4 mutations found in Kabuki syndrome and non-Hodgkin lymphoma are indicated by stars.
Extended Data Figure 5 The ternary interaction interface among MLL, RBBP5 and ASH2L.
a, Mutations of RBBP5 and ASH2L disrupted the interaction between ASH2LSPRY and RBBP5. Left, GST–RBBP5330–381 was used to pull down ASH2LSPRY and its mutants. Right, GST–ASH2LSPRY was used to pull down full-length RBBP5 and its mutants. Several control mutations (such as ASH2L(Q354A) and RBBP5(E347A)), which are not on the RBBP5–ASH2L interface, did not affect the interaction between ASH2L and RBBP5. b, ASH2L and RBBP5 mutants that disrupted the RBBP5–ASH2L interaction decreased the HKMT activities of the MLL3 complex. The activities of the mutant proteins are normalized to the wild-type MLL3–RBBP5–ASH2L complex. Mean ± s.d. (n = 3) are shown. c, Mutations of RBBP5AS residues decreased the HKMT activity of the MLL3 complex. d, Representative gel-filtration profiles for MLL and MLL mutant proteins indicate MLL mutant proteins have a similar fold to wild-type protein. e, GST–MLL3SET was used to pull down full-length RBBP5, ASH2LSPRY and their mutants. Mutations of RBBP5 Glu347 and ASH2L Gln354 in the ternary interface impaired the interaction with MLL3SET. Mutations of RBBP5AS residues (Phe336Ala, Glu338Ala/Leu339Ala) also decreased the interaction with MLL3SET to different degrees. f, RBBP5(Glu347Ala) and ASH2L(Gln354Ala) compromised the HKMT activities of all MLL complexes, indicating that RBBP5–ASH2L regulates MLL family proteins through the same mechanism. Activities of mutant complexes are normalized to the activity of wild-type MLLSET–RBBP5–ASH2L, setting at 100%. Mean ± s.d. (n = 3) are shown.
Extended Data Figure 6 Activation mechanism of MLL proteins.
a, The structure of MLL3SET is shown in cartoon diagram. The electron density (2Fo − Fc) maps (contoured at 1σ) of AdoHcy are shown. b, The structure of 
is shown in cartoon diagram. The electron density (2Fo − Fc) maps (contoured at 1σ) of AdoHcy are shown. c, Structural comparison of MLL1SET (PDB 2W5Y), 
, MLL3SET and MLL4SET (PDB 4Z4P) suggests that the SET-I motif is intrinsically flexible, and can be captured in different configurations by crystallization. There are two highly conserved glycine residues serving as hinge points that connect the SET-I motif to the rest of MLLSET. The rotation of helix αB in the SET-I motif refers to an axis defined by the two hinge points of SET-I as indicated. d, Dynamic cross-correlation matrix for motions of all Cα atoms in apo MLL3SET and MLL3SET in the M3RA complex over the course of the simulation. The right panel shows enlarged cross-correlation maps of the SET-I motif. e, Dynamic cross-correlation matrix for motions of all Cα atoms in apo 
and 
in the M1MRA complex over the course of the simulation. The right panel shows enlarged cross-correlation maps of the SET-I motif. f, The most highly correlated residues of the SET-I motif by molecular dynamics simulation are indicated by red lines. Left panel is for apo 
and right panel is for 
in the MLL1MRA complex. Red lines are connected Cα atoms for pairs of residues with calculated correlation coefficients greater than 0.55.
Extended Data Figure 7 Association of RBBP5–ASH2L increases the binding affinities of MLL to cofactor and substrate peptide.
a, ITC measurement of interactions of AdoMet with MLL3SET alone (blue) and the M3RA complex (red). The insets show the ITC titration data. b, Equilibrium dissociation constants between cofactor and MLL proteins obtained from ITC measurements. c, Fluorescence polarization assay shows that RBBP5–ASH2L increases the binding affinity between MLL3 and the H3 peptide substrate. d, Molecular dynamics simulation show dynamics of the cofactor binding pocket. Top, the distance between AdoHcy and Tyr4825; bottom, the distance between Arg4845 and Tyr4825. These distances are almost fixed in the M3RA complex, while the distances in apo MLL3 have large variations, explaining why the MLL3 complex has a higher binding affinity to cofactor than apo MLL3 does. e, The potentials of mean force for the methyl transfer reaction along the reaction coordinate range from −1.5 to 2.0 Å with an interval of 0.1 Å. It clearly shows that the MLLSET–RBBP5–ASH2L complex is more energetic favourable for the methyl transfer reaction than MLLSET alone. f, The space-filling surface model shows that the Ly4H3 binding channel exhibits open and closed conformations in the M3RA and M3RA–H3 structures.
Extended Data Figure 8 A conserved activation mechanism for SET-domain-containing HKMTs.
a, Structural comparison of MLL3SET in the M3RA–H3–AdoHcy complex, and the SET domains of CLR4 (PDB 1MVH), DIM-5 (PDB 1PEG), EZH2 (PDB 5CH1), ASH1 (PDB 3OPE) and NSD1 (PDB 3OOI). Histone H3 peptide and AdoHcy in the CLR4 structure were modelled based on the M3RA–H3–AdoHcy complex structure. RBBP5AS and the corresponding activation segments in these proteins are almost identical in overall conformation (coloured in cyan). The recently reported EZH2 complex structure also revealed such an activation segment. Most notably, an aromatic residue (shown as stick model), equivalent to Phe336 in RBBP5, stacks with another two aromatic residues to form an aromatic cage to sandwich a conserved arginine. Another conserved hydrophobic residue (shown as stick model) is also important for the stable association between the activation segment and the SET-I motif. b, Sequence alignment of the activation segments of RBBP5 and several representative HKMTs, including members from the SUV39 and SET2 families. c, Gel-filtration profiles and SDS–PAGE for DIM-5 and DIM-5ΔAS show that activation segment does not affect protein folding. DIM-5ΔAS denotes DIM-5 (residues 51–319) that does not contain the activation segment. d, HKMT activities of DIM-5 and its mutants. Activities of mutant proteins are normalized to the activity of the wild-type protein setting at 100%. Mean ± s.d. (n = 3) are shown.
and 
–RBBP5AS-ABM–ASH2LSPRY complexSupplementary information
Supplementary Figure 1
This file contains the source data for all the SDS-PAGE gels used in the paper. (PDF 9748 kb)
Normal mode analysis for MLL1SET structure
The motion pattern under mode 7 (the foremost mode) was analyzed based on apo MLL1 structure (PDB:2W5Y) and was shown in Pymol. SET-I motif is colored in orange and other part of MLL1 is colored in yellow. The angle shown is defined by Cα atoms from E3872, N3906, and C3957 on SET-I, SET-C and Post-SET respectively (colored in green). This angle was taken as the indicators to reference the amplitude of open-close movement in the cofactor-substrate-binding pocket. The most dominant motion is a clamp-like movement with the SET-I motif as the flexible moving arm, resulting in a large conformational oscillation of the substrate-binding groove between the open and closed states. (MP4 3394 kb)
Normal mode analysis for MLL1SETN3861I/Q3867L structure
The motion pattern under mode 7 (the foremost mode) was analyzed and was shown in Pymol. SET-I motif is colored in orange and other part of MLL1 is colored in yellow. The angle shown is defined by Cα atoms from E3872, N3906, and C3957 on SET-I, SET-C and Post-SET respectively (colored in green). This angle was taken as the indicators to reference the amplitude of open-close movement in the cofactor-substrate-binding pocket. The most dominant motion is a clamp-like movement with the SET-I motif as the flexible moving arm, resulting in a large conformational oscillation of the substrate-binding groove between the open and closed states. (MP4 1947 kb)
Normal mode analysis for MLL3SET structure
The motion pattern under mode 7 (the foremost mode) was analyzed and was shown in Pymol. SET-I motif is colored in orange and other part of MLL3 is colored in yellow. The angle shown is defined by Cα atoms from E4814, N4848, and C4899 on SET-I, SET-C and Post-SET respectively (colored in green). This angle was taken as the indicators to reference the amplitude of open-close movement in the cofactor-substrate-binding pocket. The most dominant motion is a clamp-like movement with the SET-I motif as the flexible moving arm, resulting in a large conformational oscillation of the substrate-binding groove between the open and closed states. (MP4 2690 kb)
Normal mode analysis for MLL1SETN3861I/Q3867L-RbBP5AS-ABM-Ash2LSPRY structure
The motion pattern under mode 7 (the foremost mode) was analyzed and was shown in Pymol. SET-I motif is colored in orange and other part of MLL1 is colored in salmon. Ash2L is in yellow and RbBP5 is in cyan. The angle shown is defined by Cα atoms from E3872, N3906, and C3957 on SET-I, SET-C and Post-SET respectively (colored in green). In sharp contrast to apo MLL1SET , SET-I motif doesn't have the clamp-like movement. as reflected by the small oscillation range of the defined angle. In this structure, SET-I motif is almost fixed, and only the rigid-body movement of whole SET domain is observed. (MP4 2136 kb)
Normal mode analysis for MLL3SET-RbBP5AS-ABM-Ash2LSPRY structure
The motion pattern under mode 7 (the foremost mode) was analyzed and was shown in Pymol. SET-I motif is colored in orange and other part of MLL3 is colored in salmon. Ash2L is in yellow and RbBP5 is in cyan. The angle shown is defined by Cα atoms from E4814, N4848, and C4899 on SET-I, SET-C and Post-SET respectively (colored in green). In sharp contrast to apo MLL3SET , SET-I motif doesn't have the clamp-like movement, as reflected by the small oscillation range of the defined angle. In this structure, SET-I motif is almost fixed, and only the rigid-body movement of whole SET domain is observed. (MP4 2092 kb)
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Li, Y., Han, J., Zhang, Y. et al. Structural basis for activity regulation of MLL family methyltransferases. Nature 530, 447–452 (2016). https://doi.org/10.1038/nature16952
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DOI: https://doi.org/10.1038/nature16952
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