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Structural insights into heme binding to IL-36α proinflammatory cytokine
Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins
Heme interaction of the intrinsically disordered N-terminal peptide segment of human cystathionine-β-synthase
Cystathionine-β-synthase (CBS) belongs to a large family of pyridoxal 5’-phosphate (PLP)-dependent enzymes, responsible for the sulfur metabolism. The heme-dependent protein CBS is part of regulatory pathways also involving the gasotransmitter hydrogen sulfide. Malfunction of CBS can lead to pathologic conditions like cancer, cardiovascular and neurodegenerative disorders. Truncation of residues 1–40, absent in X-ray structures of CBS, reduces but does not abolish the activity of the enzyme. Here we report the NMR resonance assignment and heme interaction studies for the N-terminal peptide stretch of CBS. We present NMR-spectral evidence that residues 1–40 constitute an intrinsically disordered region in CBS and interact with heme via a cysteine-proline based motif
Synthesis and Evaluation of Amyloid β Derived and Amyloid β Independent Enhancers of the Peroxidase-like Activity of Heme
Labile
heme has been suggested to have an impact in several severe
diseases. In the context of Alzheimer’s disease (AD), however,
decreased levels of free heme have been reported. Therefore, we were
looking for an assay system that can be used for heme concentration
determination. From a biochemical point of view the peroxidase activity
of the Aβ-heme complex seemed quite attractive to pursue this
goal. As a consequence, a peptide that is able to increase the readout
even in the case of a low heme concentration is favorable. The examination
of Aβ- and non-Aβ-derived peptides in complex with heme
revealed that the peroxidase-like activity significantly depends on
the peptide sequence and length. A 23mer His-based peptide derived
from human fatty acyl-CoA reductase 1 in complex with heme exhibited
a significantly higher peroxidase activity than Aβ(40)-heme.
Structural modeling of both complexes demonstrated that heme binding
via a histidine can be supported by hydrogen bond interactions of
a basic residue near the propionate carboxyl function of protoporphyrin
IX. Furthermore, the interplay of Aβ-heme and the lipoprotein
LDL as a potential physiological effector of Aβ was examined