Nucleic Acids Research, 2000, Vol. 28, No. 4 1011-1018
© 2000 Oxford University Press
Recognition of 5'-terminal TAR structure in human immunodeficiency virus-1 mRNA by eukaryotic translation initiation factor 2
Department of Molecular Virology, The Hebrew University–Hadassah Medical School, 91120 Jerusalem, Israel and 1Department of Gene Regulation and Differentiation, GBF–National Research Institute for Biotechnology, D-38124 Braunschweig, Germany
TAR, a 59 nt 5'-terminal hairpin in human immunodeficiency virus 1 (HIV-1) mRNA, binds viral Tat and several cellular proteins. We report that eukaryotic translation initiation factor 2 (eIF2) recognizes TAR. TAR and the AUG initiation codon domain, located well downstream from TAR, both contribute to the affinity of HIV-1 mRNA for eIF2. The affinity of TAR for eIF2 was insensitive to lower stem mutations that modify sequence and structure or to sequence changes throughout the remainder that leave the TAR secondary structure intact. Hence, eIF2 recognizes structure rather than sequence in TAR. The affinity for eIF2 was severely reduced by a 3 nt change that converts the single A bulge into a 7 nt internal loop. T1 footprinting showed that eIF2 protects nucleotides in the loop as well as in the strand opposite the A bulge. Thus, eIF2 recognizes the TAR loop and lower part of the sub-apical stem. Though not contiguous, these regions are brought into proximity in TAR by a bend in the helical structure induced by the UCU bulge; binding of eIF2 opens up the bulge context and apical stem. The ability to bind eIF2 suggests a function for TAR in HIV-1 mRNA translation. Indeed, the 3 nt change that reduces the affinity of TAR for eIF2 impairs the ability of reporter mRNA to compete in translation. Interaction of TAR with eIF2 thus allows HIV-1 mRNA to compete more effectively during protein synthesis.
* To whom correspondence should be addressed. Tel: +972 2 675 8389; Fax: +972 2 678 4010; Email: kaempfer@cc.huji.ac.il
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