3 -untranslated region binding proteins

MK2 (also termed MAP kinase-activated protein kinase 2, MAPKAP-K2) is activated by p38 MAP kinase a// (Kotlyarov et al, 2002 Roux and Blenis, 2004). MK2 plays a key role in the control of the production of certain cytokines, for example, tumor necrosis factor a. MK2 does so by phosphorylating proteins that bind specifically to the regulatory regions in the S untranslated regions (UTRs) of such mRNAs (Hitti et al, 2006). These regions contain AU-rich elements (AREs) to which proteins such as HnRNP A1 also bind. 

Some proteins bind directly to mRNA and act as translational repressors, many of them binding at specific sites in the 3 untranslated region (3 UTR). So positioned, these proteins interact with other translation initiation factors bound to the mRNA or with the 40S ribosomal subunit to prevent translation initiation (Fig. 28-32 compare this with Fig. 27-22). 

Czyzyk-Kreska, M.F., Z. Dominski, R. Kole, and D.E. Millhom (1994). Hypoxia stimulates binding of a cytoplasmic protein to a pyrimidine-rich sequence in the 3 -untranslated region of rat tyrosine hydroxylase mRNA. J. Biol. Chem. 269 9940-9945. 

Iron regulatory proteins (IRPs) regulate the cellular iron level in mammalian cells. IRPs are known as cytosol mRNA binding proteins which control the stability or the translation rate of mRNAs of iron metabolism-related proteins such as TfR, ferritin, and 5-aminolevulinic acid synthetase in response to the availability of cellular iron [19-21] after uptake [5]. The regulatory mechanism involves the interaction between the iron-responsive element (IRE) in the 3 or 5 untranslated regions of the transcripts and cytosolic IRPs (IRP-1 and -2). IRP-1 is an iron-sulfur (Fe-S) protein with aconitase activity containing a cubane 4Fe-4S cluster. When Fe is replete, IRP-1 prevails in a 4Fe-4S form as a holo-form and is an active cytoplasmic aconitase. As shown in Fig. 3, when Fe is deplete, it readily loses one Fe from the fourth labile Fe in the Fe-S cluster to become a 3Fe-4S cluster and in this state has little enzymatic activity [22, 23]. 

Consider ferritin first. Ferritin mRNA includes a stem-loop structure termed an iron-response element (IRE) in its 5 untranslated region (Figure 31.38). This stem-loop binds a 90-kd protein, czAlsd m IRE-bindingprotein (IRE-BP), that blocks the initiation of translation. When the iron level increases, the IRE-BP binds iron as a 4Fe-4S cluster. The IRE-BP bound to iron cannot bind RNA, because the binding sites for iron and RNA substantially overlap. Thus, in the presence of iron, ferritin mRNA is released from the IRE-BP and translated to produce ferritin, which sequesters the excess iron. 

Figure 31.38. Iron-Response Element. Ferritin mRNA includes a stem-loop structure, termed an iron-response element (IRE), in its 5 untranslated region. The IRE binds a specific protein that blocks the translation of this mRNA under low...

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