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Structural biology of poly(A) site definition

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Qin Yang, Sylvie Doublié

Published Online: Apr 27 2011

DOI: 10.1002/wrna.88

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3′ processing is an essential step in the maturation of all messenger RNAs (mRNAs) and is a tightly coupled two‐step reaction: endonucleolytic cleavage at the poly(A) site is followed by the addition of a poly(A) tail, except for metazoan histone mRNAs, which are cleaved but not polyadenylated. The recognition of a poly(A) site is coordinated by the sequence elements in the mRNA 3′ UTR and associated protein factors. In mammalian cells, three well‐studied sequence elements, UGUA, AAUAAA, and GU‐rich, are recognized by three multisubunit factors: cleavage factor I_m (CFI_m), cleavage and polyadenylation specificity factor (CPSF), and cleavage stimulation factor (CstF), respectively. In the yeast Saccharomyces cerevisiae, UA repeats and A‐rich sequence elements are recognized by Hrp1p and cleavage factor IA. Structural studies of protein–RNA complexes have helped decipher the mechanisms underlying sequence recognition and shed light on the role of protein factors in poly(A) site selection and 3′ processing machinery assembly. In this review we focus on the interactions between the mRNA cis‐elements and the protein factors (CFI_m, CPSF, CstF, and homologous factors from yeast and other eukaryotes) that define the poly(A) site. WIREs RNA 2011 2 732–747 DOI: 10.1002/wrna.88

Figure 1.

Schematic representation of the (a) mammalian and (b) yeast 3′ processing machinery. The RNA cis‐elements are shown in magenta. Homologous protein factors in yeast and mammals are depicted in the same color.

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Figure 2.

Cleavage factor I_m (CFI_m). (a) Domain organization of CFI_m subunits CFI_m25 and CFI_m68. (b) Crystal structure of the CFI_m25/CFI_m68 RRM/RNA complex (PDB ID: 3Q2T). The CFI_m25 homodimer is colored in green and lime. The highly conserved loop/helix motif (residues 51–76) is highlighted in brown. Each CFI_m25 monomer binds to one UGUA element, shown as a stick model and colored in yellow and salmon. CFI_m68 monomers are colored in blue and cyan. The additional C‐terminal α‐helix of the RRM is highlighted in gold. (c) Close‐up view of the CFI_m25‐UGUA interactions. The protein and RNA are colored as in (b). Hydrogen bonds are represented by red dashed lines.

[ Normal View 61K | Magnified View 108K ]

Figure 3.

Cleavage and polyadenylation specificity factor (CPSF). (a) Crystal structure of the archaeal Pyrococcus horikoshii CPSF73 in complex with RNA (PDB ID: 3AF631). The KH domain, metallo‐β‐lactamase (MBL) domain, and β‐CASP domain are shown in cartoon mode, with α‐helices in cylindrical representation, and colored in red, blue, and yellow, respectively. The RNA is shown as a stick model (yellow). The two zinc ions are depicted as green spheres. (b) Crystal structures of human CPSF73 (2I7V30) and yeast CPSF100 (Ydh1) (2I7X30). MBL and β‐CASP domains are shown in blue and yellow, respectively, for CPSF73, and in cyan and green, respectively, for CPSF100 (Ydh1). The zinc ions and sulfate bound by CPSF73 are shown. The position and orientation of CPSF73 and CPSF100 are based on the superposition with the RNase J homodimer. (c) Domain organization of CPSF subunits and RNase J. (d) Homodimer conformation of RNase J (3BK191).

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Figure 4.

Cleavage stimulation factor (CstF). (a) Crystal structure of the CstF77 homodimer (2OOE37). The HAT‐N domain is shown in green. The HAT‐C domain, which is involved in dimerization, is shown in yellow. The second monomer in the dimer is shown in gray. (b) Structure of human CstF64 (1P1T33) and the yeast CstF64 homolog Rna15p/RNA complex (2X1A, 2X1F34). Two RNA molecules bound at sites I and II are shown in tan and yellow, respectively. (c) A crystal structure of a seven‐blade WD40 domain from Prp19 (3LRV114) is presented as a reference for the size and shape of CstF50. (d) Crystal structure of the CstF50 N‐terminal dimerization domain (2XZ238). (e) A model for the hexameric architecture (2:2:2 stoichiometry) of the CstF complex. The second monomer in the dimers is labeled with a prime (′) symbol. The atomic structures are represented on the same scale. (f) Domain organization of the CstF subunits.

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Figure 5.

Hrp1p. (a) NMR structure of the Hrp1p–Rna15p–RNA complex (2KM854). Hrp1p RRM1 and RRM2 are shown in salmon and magenta, respectively. Rna15p RRM is colored in cyan. The RNA molecule is shown in yellow. (b) Domain organization of Hrp1p.

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Yingqun Huang

and her research team focus on the dissection of the molecular mechanisms and pathways involved in Lin28-mediated regulation. First, they will analyze Lin28 expression in mouse and human ES cells to determine whether its expression is regulated during the cell cy-cle. Then, they will characterize the interactions between Lin28 and its associated mRNAs to gain molecular insights into their assembly, function and regulation in the cellular milieu. Finally, they will strive to identify Lin28-interacting protein partners and new target mRNAs to establish a comprehensive and global understanding of Lin28 function.

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Article Title	Structural biology of poly(A) site definition
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