The broad diversity of heme-protein cross-links: An overview

Heme proteins perform a large array of biological functions using the same heme cofactor. A primary method of regulating these diverse functions is the heme-protein cross-link, an important post-translational modification. This review presents an overview of the broad diversity of heme-protein cross-links, including Cys/SeCys -heme, Met-heme, His-heme, Trp/Tyr-heme, Glu/Asp-heme and Lys-heme cross-links, which have been discovered in the last three decades, with bond type ranging from C-S, C-Se, C-N, C-C to C-O. Many advances have been made in revealing the mechanisms of heme-protein cross-link formation, as well as the structural and functional roles. Moreover, most of these cross-links have been successfully recreated in natural or de novo proteins. These tremendous progresses have not only enhanced our knowledge of how cross-links fine-tune the structure and function of natural heme proteins, but also provided us powerful strategies for design of artificial heme proteins with functionalities beyond those of natural heme proteins.