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Structural basis for nuclear import of splicing factors by human Transportin 3
Authors:
Goedele
Maertens
(Imperial College London)
,
N. J.
Cook
(Imperial College London)
,
Weifeng
Wang
(DanaFarber Cancer Institute, Boston)
,
Stephen
Hare
(Imperial College London)
,
Saumya
Gupta
(Imperial College London)
,
Ilker
Oztop
(DanaFarber 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
(DanaFarber 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