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

Monday, 25 May 2015: 09:00
Lake Michigan (Hilton Chicago)
D. Imhof, T. Kühl (University of Bonn), N. Goradia (Leibniz Institute for Age Research), H. H. Brewitz, A. Wißbrock (University of Bonn), and O. Ohlenschläger (Leibniz Institute for Age Research)
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].


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5. Kühl, T., Wißbrock, A., Goradia, N., Sahoo, N., Galler, K., Neugebauer, U., Popp, J., Heinemann, S.H., Ohlenschläger, O., Imhof, D., ACS Chem. Biol. 2013, 8, 1785-1793.

6. Kühl, T., Imhof, D., Chembiochem 2014, 15, 2024-2035.

7.  Brewitz, H.H., Kühl, T., Goradia, N., Galler, K., Popp, J., Neugebauer, U., Ohlenschläger, O., Imhof, D., submitted.