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J. Biol. Chem., Vol. 283, Issue 40, 27130-27143, October 3, 2008

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Functional Significance of the Interaction between the mRNA-binding Protein, Nab2, and the Nuclear Pore-associated Protein, Mlp1, in mRNA Export^*

Milo B. Fasken, Murray Stewart, and Anita H. Corbett¹

From the Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322 and the MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom

Nuclear export of mRNA requires several key mRNA-binding proteins that recognize and remodel the mRNA and target it for export via interactions with the nuclear pore complex. In Saccharomyces cerevisiae, the shuttling heterogeneous nuclear ribonucleoprotein, Nab2, which is essential for mRNA export, specifically recognizes poly(A) RNA and binds to the nuclear pore-associated protein, myosin-like protein 1 (Mlp1), which functions in mRNA export and quality control. Specifically, the N-terminal domain of Nab2 (Nab2-N; residues 1–97) interacts directly with the C-terminal globular domain of Mlp1 (CT-Mlp1: residues 1490–1875). Recent structural and binding studies focused on Nab2-N have shown that Nab2-N contains a hydrophobic patch centered on Phe⁷³ that is critical for interaction with Mlp1. Engineered amino acid changes within this patch disrupt the Nab2/Mlp1 interaction in vitro. Given the importance of Nab2 and Mlp1 to mRNA export, we have examined the Nab2/Mlp1 interaction in greater detail and analyzed the functional consequences of disrupting the interaction in vivo. We find that the Nab2-binding domain of Mlp1 (Mlp1-NBD) maps to a 183-residue region (residues 1586–1768) within CT-Mlp1, binds directly to Nab2 with micromolar affinity, and confers nuclear accumulation of poly(A) RNA. Furthermore, we show that cells expressing a Nab2 F73D mutant that cannot interact with Mlp1 exhibit nuclear accumulation of poly(A) RNA and that this nab2 F73D mutant genetically interacts with alleles of two essential mRNA export genes, MEX67 and YRA1. These data provide in vivo evidence for a model of mRNA export in which Nab2 is important for targeting mRNAs to the nuclear pore for export.

Received for publication, May 12, 2008 , and in revised form, July 29, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (to A. H. C.). This work was also supported by a Wellcome Trust Programme Grant (to M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

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¹ To whom correspondence should be addressed: 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-4546; Fax: 404-727-2738; E-mail: acorbe2{at}emory.edu.

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