Post-transcriptional regulation of messenger RNA (mRNA) stability and translation are important control points for gene expression. The overall goal of this project is to generate and utilize structural information to enhance our understanding of these processes. One mechanism for regulation of mRNA stability involves the presence of adenosine-uridine (AU)-rich elements (AREs) in the 3-prime untranslated regions of many short-lived mRNAs. These AREs are found in mRNAs encoding proto-oncogenes, cytokines, and lymphokines and mediate their rapid degradation. The Hu proteins, human homologues of the Drosophila protein ELAV (embryonic lethal, abnormal visual), bind to AREs and stabilize the mRNAs to which they bind. One of the objectives of this project is to determine the three-dimensional structures of Hu protein RNA recognition motif (RRM) domains bound to RNA elements to understand how Hu proteins specifically recognize their RNA partners, examine how the protein-RNA interactions may stabilize the mRNA, and provide insight into how over 1000 proteins utilize the RRM protein scaffold to recognize different RNA sequences. We have recently determined a 1.8 angstrom crystal structure of an ARE-binding fragment of HuD in complex with a fragment of the cfos ARE, a class I ARE, and a 2.3 angstrom crystal structure of the same fragment of HuD bound to a minimal fragment of the tumor necrosis factor a ARE, a class II ARE. These structures revealed a consensus RNA recognition sequence for HuD that highlights the importance of some bases, but the relative lack of specificity at other positions. Comparison to structures of other proteins containing RRM domains revealed that although these domains bind to different RNA structures (e.g. single-stranded RNA, stem-loop RNA) and sequences, a common binding mode using two nucleotide binding pockets is observed in all RRM domain structures.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
United States
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Cheong, Cheom-Gil; Hall, Traci M Tanaka (2006) Engineering RNA sequence specificity of Pumilio repeats. Proc Natl Acad Sci U S A 103:13635-9
Hall, Traci M Tanaka (2005) Structure and function of argonaute proteins. Structure 13:1403-8
Hall, Traci M Tanaka (2005) Multiple modes of RNA recognition by zinc finger proteins. Curr Opin Struct Biol 15:367-73
Hall, Traci M Tanaka (2003) SAM breaks its stereotype. Nat Struct Biol 10:677-9
Vargason, Jeffrey M; Szittya, Gyorgy; Burgyan, Jozsef et al. (2003) Size selective recognition of siRNA by an RNA silencing suppressor. Cell 115:799-811
Hall, Traci M Tanaka (2002) Poly(A) tail synthesis and regulation: recent structural insights. Curr Opin Struct Biol 12:82-8
Wang, X; Zamore, P D; Hall, T M (2001) Crystal structure of a Pumilio homology domain. Mol Cell 7:855-65
Wang, X; Tanaka Hall, T M (2001) Structural basis for recognition of AU-rich element RNA by the HuD protein. Nat Struct Biol 8:141-5