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Updated: Apr 30, 2026
08:48
Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays
Published on: November 29, 2014
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Substrate selectivity of human histidine methyltransferase METTL9
Sadaf Ahmad1, Laust Moesgaard1, Christian W Tornøe2
1Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
Protein Science : a Publication of the Protein Society
|April 29, 2026
Summary
Histidine methyltransferase METTL9 specifically methylates zinc transporter SLC39A5. The xHxH motif is crucial for METTL9 catalysis, revealing its narrow substrate selectivity for biomedical insights.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Histidine methylation by histidine methyltransferase (HMT) METTL9 modifies zinc transporter function.
- Zinc transporters play critical roles in metal homeostasis and cellular processes.
Purpose of the Study:
- To investigate the substrate specificity of human METTL9 on zinc transporter SLC39A5.
- To elucidate the structural basis for METTL9-SLC39A5 interaction and catalysis.
Main Methods:
- Synthetic peptide modification and enzymatic assays.
- Computational studies including molecular dynamics simulations.
- Analysis of METTL9-catalyzed Nπ-methylation of His375 in SLC39A5-derived peptides.
Main Results:
- The xHxH motif (residues 372-375) is essential for METTL9 catalysis.
- Human METTL9 exhibits narrow substrate specificity for His375, not methylating simple histidine mimics.
- METTL9 recognizes specific non-natural amino acids at position 373 and limited mimics at positions 372 and 374.
Conclusions:
- Human METTL9 possesses distinct substrate selectivities, highlighting the importance of the xHxH motif.
- Understanding METTL9 substrate scope is vital for basic molecular and biomedical research.
- Structural insights support the significance of the xHxH motif for METTL9-SLC39A5 complex stability and catalysis.
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