Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin

Hintzen, Jordi C. J.; Ma, Huida; Deng, Hao; Witecka, Apolonia; Andersen, Steffen B.; Drozak, Jakub; Guo, Hong; Qian, Ping; Li, Haitao; Mecinović, Jasmin

doi:10.1002/pro.4305

Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin

Journal Article · Tue Apr 12 00:00:00 EDT 2022 · Protein Science

DOI:https://doi.org/10.1002/pro.4305· OSTI ID:2471404

Hintzen, Jordi C. J. ^[1]; Ma, Huida ^[2]; Deng, Hao ^[3]; Witecka, Apolonia ^[4]; Andersen, Steffen B. ^[1]; Drozak, Jakub ^[4]; Guo, Hong ^[5]; Qian, Ping ^[3]; Li, Haitao ^[2]; ^[1]

University of Southern Denmark, Odense (Denmark)
Tsinghua University, Beijing (China)
Shandong Agricultural University, Tai'an (China)
University of Warsaw (Poland)
University of Tennessee, Knoxville, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Actin histidine N^τ-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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: European Research Council (ERC); Narodowe Centrum Nauki (NCN); National Key Research Development Program of China; National Natural Science Foundation of China (NSFC); Natural Science Foundation of Shandong Province; USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2471404

Journal Information:: Protein Science, Journal Name: Protein Science Journal Issue: 5 Vol. 31; ISSN 0961-8368

Publisher:: Wiley -- The Protein SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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