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Heme-regulated eukaryotic initiation factor 2a (eIF2a) kinase (HRI), functions in response to heme shortage in reticulocytes and aids in the maintenance of a heme:globin ratio of 1:1. Under normal conditions, heme binds to HRI and blocks its function. | 1FEBS Journal Autophosphorylation of heme-regulated eukaryotic initiation factor 2a kinase and the role of the modification in catalysis Jotaro Igarashi1 z Takehiko Sasaki1 z Noriko Kobayashi2 Shinji Yoshioka2 Miyuki Matsushita2 and Toru Shimizu1 1 Institute of Multidisciplinary Research for Advanced Materials Tohoku University Sendai Japan 2 Bio-MedicalCenter R D Division Nanotechnology Product Business Group Hitachi High-Technologies Corporation Hitachinaka Ibaraki Japan Keywords autophosphorylation eIF2a kinase heme mass spectrometry mutation Correspondence J. Igarashi Institute of Multidisciplinary Research for Advanced Materials Tohoku University 2-1-1 Katahira Aoba-ku Sendai 980-8577 Japan Fax 81 22 217 5605 Tel 81 22 217 5605 E-mail jotaro@tagen.tohoku.ac.jp These authors contributed equally to this work Received 2 September 2010 revised 23 November 2010 accepted 7 January 2011 doi 10.1111 j.1742-4658.2011.08007.x Heme-regulated eukaryotic initiation factor 2a eIF2a kinase HRI functions in response to heme shortage in reticulocytes and aids in the maintenance of a heme globin ratio of 1 1. Under normal conditions heme binds to HRI and blocks its function. However during heme shortage heme dissociates from the protein and autophosphorylation subsequently occurs. Autophosphorylation comprises a preliminary critical step before the execution of the intrinsic function of HRI specifically phosphorylation of Ser-51 of eIF2a to inhibit translation of the globin protein. The present study indicates that dephosphorylated mouse HRI exhibits strong intramolecular interactions between the N-terminal and C-terminal domains compared to phosphorylated HRI. It is therefore suggested that autophosphorylation reduces the intramolecular interaction which induces irreversible catalytic flow to the intrinsic eIF2a kinase activity after heme dissociates from the protein. With the aid of MS we identified 33 phosphorylated sites in mouse HRI overexpressed in Escherichia coli. .
