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Structural basis for nuclear import of splicing factors by human Transportin 3

DOI: 10.1073/pnas.1320755111 DOI Help

Authors: Goedele Maertens (Imperial College London) , N. J. Cook (Imperial College London) , Weifeng Wang (Dana–Farber Cancer Institute, Boston) , Stephen Hare (Imperial College London) , Saumya Gupta (Imperial College London) , Ilker Oztop (Dana–Farber Cancer Institute, Boston) , Kyeong Eun Lee (National Cancer Institute, Frederick) , Valerie Pye (Cancer Research UK) , Ophelie Cosnefroy (Imperial College London) , Ambrosius P. Snijders (Imperial College London) , Vineet N. Kewalramani (National Cancer Institute, Frederick) , Ariberto Fassati (University College London) , Alan Engelman (Dana–Farber Cancer Institute, Boston) , Peter Cherepanov (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 111 (7) , PAGES 2728 - 2733

State: Published (Approved)
Published: February 2014
Diamond Proposal Number(s): 9424

Abstract: Transportin 3 (Tnpo3, Transportin-SR2) is implicated in nuclear import of splicing factors and HIV-1 replication. Herein, we show that the majority of cellular Tnpo3 binding partners contain arginine-serine (RS) repeat domains and present crystal structures of human Tnpo3 in its free as well as GTPase Ran- and alternative splicing factor/splicing factor 2 (ASF/SF2)-bound forms. The flexible β-karyopherin fold of Tnpo3 embraces the RNA recognition motif and RS domains of the cargo. A constellation of charged residues on and around the arginine-rich helix of Tnpo3 HEAT repeat 15 engage the phosphorylated RS domain and are critical for the recognition and nuclear import of ASF/SF2. Mutations in the same region of Tnpo3 impair its interaction with the cleavage and polyadenylation specificity factor 6 (CPSF6) and its ability to support HIV-1 replication. Steric incompatibility of the RS domain and RanGTP engagement by Tnpo3 provides the mechanism for cargo release in the nucleus. Our results elucidate the structural bases for nuclear import of splicing factors and the Tnpo3–CPSF6 nexus in HIV-1 biology.

Journal Keywords: Sr Protein; Transportin-Sr; Host Factor; Importin

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF