A Chemical Proteomic Map of Heme–Protein Interactions

Heme is an essential cofactor for many human proteins
as well as
the primary transporter of oxygen in blood. Recent studies have also
established heme as a signaling molecule, imparting its effects through
binding with protein partners rather than through reactivity of its
metal center. However, the comprehensive annotation of such heme-binding
proteins in the human proteome remains incomplete. Here, we describe
a strategy which utilizes a heme-based photoaffinity probe integrated
with quantitative proteomics to map heme–protein interactions
across the proteome. In these studies, we identified 350+ unique heme–protein
interactions, the vast majority of which were heretofore unknown and
consist of targets from diverse functional classes, including transporters,
receptors, enzymes, transcription factors, and chaperones. Among these
proteins is the immune-related interleukin receptor-associated kinase
1 (IRAK1), where we provide preliminary evidence that heme agonizes
its catalytic activity. Our findings should improve the current understanding
of heme’s regulation as well as its signaling functions and
facilitate new insights of its roles in human disease.