Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin

Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its...

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Published in:Protein science 2022-05, Vol.31 (5), p.e4305-n/a
Main Authors: Hintzen, Jordi C. J., Ma, Huida, Deng, Hao, Witecka, Apolonia, Andersen, Steffen B., Drozak, Jakub, Guo, Hong, Qian, Ping, Li, Haitao, Mecinović, Jasmin
Format: Article
Language:English
Subjects:
Actin
Actins - chemistry
Actins - metabolism
biocatalysis
Computer applications
Free energy
Full‐length Paper
Full‐length Papers
Histidine
Histidine - chemistry
Histone Methyltransferases - chemistry
Histone Methyltransferases - metabolism
Humans
Methylation
Methyltransferase
Methyltransferases - metabolism
Molecular chains
Molecular dynamics
Nucleophiles
Peptides
Quantum mechanics
SETD3
Substrates
β‐actin
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Summary:Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N‐nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical molecular dynamics and free‐energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic, and functional insight into actin histidine methylation by SETD3. PDB Code(s): 7W28 and 7W29
ISSN:0961-8368
1469-896X
1469-896X
DOI:10.1002/pro.4305