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Structural insights into the interaction of heme with protein tyrosine kinase JAK2

Janus kinase 2 (JAK2) is the most important signal transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal ion-carrying molecule, which is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 represent heme-regulatory motifs and show low micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein may facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders.