Protein histidine methylation - molecular mechanisms and biological significance

Thousands of proteins perform tasks necessary for a cell, organ, or whole body to function. Some are enzymes that catalyze biochemical reactions, others are part of structures that give the cells their shape, whereas others again are involved in regulating the cell's processes or in transmitting signals in and between cells. Each protein consists of different amino acids that are joined together in a given order (this order is defined by the DNA sequence in the genes) and there are 20 different amino acids. The function of the proteins is further regulated and optimized by adding some additional chemical groups to the amino acids, e.g. methyl groups or phosphate groups. Protein methylation most often occurs on the amino acids called arginine and lysine, and is performed by specialized enzymes, called methyltransferases. So far, protein methylation has been most studied for so-called histone proteins, which are a major component of the chromosomes. Histone methylation was shown to be important in epigenetics, i.e. to regulate how chromosomes are organized and whether genes are turned on or off. In this project, we will study another type of protein methylation, namely that of the amino acid histidine. Histidine methylation was discovered over 50 years ago, but few details have been known, and it is now understood that this is more important and more common than previously thought. We recently discovered a new methyltransferase that performs histidine methylation in human cells, and we have also found that proteins that take part in many of the body's important processes (e.g., energy conversion, transport of trace elements and immune systems) are subject to histidine methylation. In this project, we will both explore the biological significance of histidine methylation, and we will try to identify new methyltransferases involved in this. In the longer term, this project could have an impact on the development of new treatment methods and diagnostic tools for disease. We recently published two research articles that describe two novel histidine methyltransferases in humans (only one such enzyme was described previously).

The function of a protein is largely determined by its amino acid sequence, defined by the DNA sequence of the encoding gene. In addition, protein function can be further regulated or optimized by the attachment of small chemical modifications to the amino acids, such as methylations and phosphorylations. Protein methylation is introduced by highly specific methyltransferase (MTase) enzymes, and occurs most frequently on the amino acids arginine and lysine, but can also be found on other amino acids. So-called histone proteins are associated with DNA in chromosomes, and lysine methylations on histones are important regulators of gene expression and chromosome packing. We have during the last decade discovered various novel MTases enzymes involved in protein lysine methylation, but will here focus on another amino acid, namely histidine. Protein histidine methylation was first reported about 50 years ago, but still remains largely unexplored. However, we have recently discovered (unpublished findings) a novel human MTase that methylates histidines in proteins, and histidine methylation appears to be a relatively frequent protein modification. The project will encompass the identification of novel MTases involved in protein histidine methylation in humans, and also investigate how methylation may affect the targeted protein and relevant cellular processes. In particular, histidines in proteins are frequently involved in binding certain metals, such as zinc, and there are indications that histidine methylation may modulate zinc-binding proteins. Therefore, we will also explore the possibility that histidine methylation represents a novel mechanism for regulating cellular zinc homeostasis, which is a tightly regulated process. Many MTases have been shown to be mutated or perturbed in human disease, and obtaining novel insights into the mechanisms and functional consequences of protein histidine methylation in humans may have important applications within medicine.