A decrease in the level of heme leads to a reduction in globin synthesis in reticulocytes. Which of the following best explains this phenomenon?
Correct Answer: The initiation factor eIF-2 becomes phosphorylated,reducing its level of activity
Description: One mechanism by which initiation of translation in eukaryotes is effected is by phosphorylation of a small set (S) residue in the alpha subunit of eIF-2. The factor eIF-2 requires activation by interaction with GTP. The energy of GTP hydrolysis is used during translational initiation, thereby allowing eIF-2 to have GDP bound instead of GTP. In order to reactivate eIF-2, the GDP must be exchanged for DTP. This requires an additional protein of the guanine-nucleotide exchange factor (GEF) family known as eIF-2B. The phosphorylated form of eIF-2, in the absence of the eIF-2B, is just as active an initiator of translation as the non-phosphorylated form. However, when eIF-2 is phosphorylated, the GDP-bound complex is stabilized and exchanged for GTP is inhibited. When eIF-2 is phosphorylated, it binds eIF-2B more tightly, thus slowing the rate of exchange. It is this inhibited exchange that affects the rate of initiation. Within reticulocytes, the phosphorylation of eIF-2 is the result of the activity called heme-controlled inhibitor (HCI). Ref: Kennelly P.J., Rodwell V.W. (2011). Chapter 6. Proteins: Myoglobin & Hemoglobin. In D.A. Bender, K.M. Botham, P.A. Weil, P.J. Kennelly, R.K. Murray, V.W. Rodwell (Eds), Harper's Illustrated Biochemistry, 29e.
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Biochemistry
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