Abstract
Deviant levels of available heme and related molecules can result from pathological situations such as impaired heme biosynthesis or increased hemolysis as a consequence of vascular trauma or bacterial infections. Heme-related biological processes are affected by these situations, and it is essential to fully understand the underlying mechanisms. While heme has long been known as an important prosthetic group of various proteins, its function as a regulatory and signaling molecule is poorly understood. Diseases such as porphyria are caused by impaired heme metabolism, and heme itself might be used as a drug in order to downregulate its own biosynthesis. In addition, heme-driven side effects and symptoms emerging from heme-related pathological conditions are not fully comprehended and thus impede adequate medical treatment. Several heme-regulated proteins have been identified in the past decades, however, the molecular basis of transient heme-protein interactions remains to be explored. Herein, we summarize the results of an in-depth analysis of heme binding to proteins, which revealed specific binding modes and affinities depending on the amino acid sequence. Evaluating the binding behavior of a plethora of heme-peptide complexes resulted in the implementation of a prediction tool (SeqD-HBM) for heme-binding motifs, which eventually led and will perspectively lead to the identification and verification of so far unknown heme-regulated proteins. This systematic approach resulted in a broader picture of the alternative functions of heme as a regulator of proteins. However, knowledge on heme regulation of proteins is still a bottomless barrel that leaves much scope for future research and development.
Highlights
Heme is a valued, versatile, and vital molecule [1,2,3]
Sequence criteria for heme binding identified by a combinatorial peptide library screening Since short protein-derived sequences (∼9 amino acids) were shown to be suitable to study heme-binding behavior [9,12,27,28], our initial studies included the construction of a combinatorial nonapeptide library based on histidine, tyrosine, and cysteine as heme axial ligand as these are the most striking heme-coordinating residues (Figure 1A) [29]
All the information gained from UV/Vis, resonance Raman (rRaman), continuous wave electron spin resonance (cwEPR), and 2D-NMR spectroscopy revealed insight into the specific characteristics of heme binding to peptides/proteins on the level of primary sequences and secondary structures
Summary
Versatile, and vital molecule [1,2,3]. As a prosthetic group of hemoglobin, heme was initially described by Fritz Ludwig Hunefeld in the 1840s [4]. Sequence criteria for heme binding identified by a combinatorial peptide library screening Since short protein-derived sequences (∼9 amino acids) were shown to be suitable to study heme-binding behavior [9,12,27,28], our initial studies included the construction of a combinatorial nonapeptide library based on histidine, tyrosine, and cysteine as heme axial ligand (at position P0) as these are the most striking heme-coordinating residues (Figure 1A) [29]. The formation of heme-peptide/protein complexes is detectable in the UV/Vis spectrum, in particular with regard to a shift of the Soret-band as is commonly observed for heme binding to amino acid sequences.
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