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Structural analysis of an active fungal PRC2.

ABSTRACT: Crystal structure determination of an active polycomb repressive complex 2 (PRC2) from a thermophilic fungus, Chaetomium thermophilum, revealed some long-sought structural mechanisms for assembly, catalysis, and regulation of this important enzyme complex, responsible for trimethylation of histone H3K27 (H3K27me3) and silencing of developmentally regulated genes. In light of the crystal structures of the fungal PRC2 captured in the basal and H3K27me3-stimulated states as well as the structural analysis published previously, (1) we examined surface conservation and electrostatic potential distribution to provide additional insights into functional similarity and divergence between the fungal and human PRC2 and for PRC2 binding by nucleic acids. Structure comparison indicated a conformational change of the catalytic SET domain within PRC2 during transition from the inactive to active state. This conserved structural mechanism is also used by another histone methyltransferase family associated with gene activation for enzyme regulation and may underlie the allosteric stimulation of PRC2 as well.

SUBMITTER: Jiao L

PROVIDER: S-EPMC4991241 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Structural analysis of an active fungal PRC2.

Jiao Lianying L Liu Xin X

Nucleus (Austin, Tex.) 20160517 3

Crystal structure determination of an active polycomb repressive complex 2 (PRC2) from a thermophilic fungus, Chaetomium thermophilum, revealed some long-sought structural mechanisms for assembly, catalysis, and regulation of this important enzyme complex, responsible for trimethylation of histone H3K27 (H3K27me3) and silencing of developmentally regulated genes. In light of the crystal structures of the fungal PRC2 captured in the basal and H3K27me3-stimulated states as well as the structural a ...[more]

PMID: 27187637

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Project description:Native thermolysin binds a single catalytically essential zinc ion that is tetrahedrally coordinated by three protein ligands and a water molecule. During catalysis the zinc ligation is thought to change from fourfold to fivefold. Substitution of the active-site zinc with Cd2+, Mn2+, Fe2+, and Co2+ alters the catalytic activity (Holmquist B, Vallee BL, 1974, J Biol Chem 249:4601-4607). Excess zinc inhibits the enzyme. To investigate the structural basis of these changes in activity, we have determined the structures of a series of metal-substituted thermolysins at 1.7-1.9 A resolution. The structure of the Co(2+)-substituted enzyme is shown to be very similar to that of wild type except that two solvent molecules are liganded to the metal at positions that are thought to be occupied by the two oxygens of the hydrated scissile peptide in the transition state. Thus, the enhanced activity toward some substrates of the cobalt-relative to the zinc-substituted enzyme may be due to enhanced stabilization of the transition state. The ability of Zn2+ and Co2+ to accept tetrahedral coordination in the Michaelis complex, as well as fivefold coordination in the transition state, may also contribute to their effectiveness in catalysis. The Cd(2+)- and Mn(2+)-substituted thermolysins display conformational changes that disrupt the active site to varying degrees and could explain the associated reduction of activity. The conformational changes involve not only the essential catalytic residue, Glu 143, but also concerted side-chain rotations in the adjacent residues Met 120 and Leu 144. Some of these side-chain movements are similar to adjustments that have been observed previously in association with the "hinge-bending" motion that is presumed to occur during catalysis by the zinc endoproteases. In the presence of excess zinc, a second zinc ion is observed to bind at His 231 within 3.2 A of the zinc bound to native thermolysin, explaining the inhibitory effect.

Dataset Information

Structural analysis of an active fungal PRC2.

Publications

Structural analysis of an active fungal PRC2.

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