Zinc transport regulation through histidine methylation

Zinc is an essential micronutrient required for the function of hundreds of proteins involved in a wide range of biological processes. After intake of zinc from the diet, its levels in the human body are tightly regulated by the absorption, secretion via specialized zinc transporter proteins in the intestine. Any imbalance is detrimental to human health, with the intestine being particularly sensitive to zinc fluctuations, which affect the integrity of the intestinal barrier and lead to inflammatory diseases and cancers of the bowel. On the molecular level, the precise mechanisms orchestrating the function of different zinc transporter proteins are still unclear. In humans, there are over twenty such proteins, the majority of which contain regions rich in the amino acid histidine. These histidines are speculated to play a crucial role in binding and interacting specifically with zinc. Recently, we discovered an enzyme that tweaks these regions by adding methyl groups to the histidine residues, and showed that methylated histidines have less affinity for zinc. This project aims to identify novel mechanisms regulating zinc levels through histidine methylation of zinc transporters, to develop research tools for efficient study of histidine methylation, and to pave the way for novel treatments of intestinal diseases.

The delicate balance of zinc levels in the body is essential for human health. Zinc is absorbed and excreted via intestinal zinc transporter proteins, and perturbations of this process are associated with pathologies, including inflammatory diseases and cancers of the bowel. The precise molecular mechanisms regulating zinc transport, however, remain a major knowledge gap. Based on the recent discovery of an enzyme methylating histidine residues in zinc transporters, and drawing on preliminary findings which demonstrate reduced affinity of methylated histidines to zinc, this project aims to identify novel mechanisms regulating zinc homeostasis through histidine methylation. We will examine the regulation and effect of histidine methylation on zinc transport in intestinal cell culture and organoids, and examine how knockout of the methylhistidine-generating enzyme affects the integrity and pathology of the intestinal tract in mouse models. In addition, we will identify reader proteins specifically recognizing methylhistidines and develop anti-methylhistidine antibodies and inhibitors to use as tools for detection, enrichment, and inhibition of histidine methylation. Such tools are urgently needed by the international research community, as none are currently available commercially. Overall, this project will lead to great advances in the field of protein regulation, and may uncover novel mechanisms in intestinal zinc transport and pathology.