Iron(III) Protoporphyrin IX Associates with Proteins in a Sequence-Dependent Manner

Abstract

The role and action of heme as a regulatory effector of proteins came more and more into the focus of biochemical research aiming at a complete understanding of this molecule’s function in the organism apart from its well-investigated embedment in hemoproteins, which e.g. are involved in gas transport, catalytic reactions or electron transfer [1-3]. Transient binding of regulatory heme to proteins might significantly change a protein's function. Distinct sequence stretches on the protein surface are responsible for interaction with heme. As a consequence of association, conformational changes within the protein may lead to changes in the protein's activity [4]. Interactions between heme and characteristic iron-coordinating amino acids (cysteine, histidine, tyrosine) are well-known. In addition, however, the surrounding amino acids contribute to the association of the protein with the protoporphyrin ring system. This fact was confirmed by results of a combinatorial peptide library screening [1]. Based on these data we predicted motifs for heme binding as well as proteins as possible targets, such as dipeptidyl peptidase 8 which subsequently was proven to be inhibited by heme [5]. Further targets possessing a great potential as heme-regulated proteins are currently under investigation. In-depth structural studies e.g. using UV-vis, resonance Raman, and NMR spectroscopy revealed the existence of different binding modes for heme-peptide/protein complexes [6]. These investigations resulted in the first structures of heme-peptide complexes known so far [5,7]. Binding data and structural characteristics displayed specific sequence requirements that, in turn, present suitable tools to identify potential heme-regulated proteins and, moreover, open new perspectives for diagnosis and treatment of pathophysiological conditions associated with non-balanced concentrations of bound and free regulatory heme in the organism [6].