dictyNews
Electronic Edition
Volume 41, number 22
October 23, 2015

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Abstracts
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Mechanism of eIF6 release from the nascent 60S ribosomal subunit

Félix Weis1,2,3,4, Emmanuel Giudice5, Mark Churcher2,3,4, Li Jin2,3,4,6, Christine
Hilcenko1,2,3,4, Chi C. Wong7, David Traynor6, Robert R. Kay6, Alan J. Warren1,2,3,4

1Cambridge Institute for Medical Research, Cambridge, UK.
2Medical Research Council Laboratory of Molecular Biology, University of
Cambridge Research Unit, Cambridge, UK
3The Department of Haematology, University of Cambridge, Cambridge, UK.
4Wellcome Trust-Medical Research Council Stem Cell Institute, University of
Cambridge, Cambridge, UK.
5Université de Rennes 1, Centre Nationale de la Recherche Scientifique, Unité Mixte
de Recherche 6290, Institut de Génétique et Développement de Rennes, Rennes,
France.
6Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
7Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.


Nature Structural and Molecular Biology, in press

SBDS (deficient in the inherited leukemia predisposition disorder Shwachman-
Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S
ribosomal subunits for translation by catalyzing eviction of the anti-association factor 
eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely
unknown. Here, we present cryo-electron microscopy structures of human SBDS and
SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and
without endogenous eIF6. SBDS assesses the integrity of the P-site, bridging uL16
(mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and
the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69,
promoting a conformational switch in EFL1 that displaces eIF6 by competing for an
overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved
mechanism of eIF6 release that is corrupted in both inherited and sporadic leukemias.


Submitted by Rob Kay [[log in to unmask]]
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[End dictyNews, volume 41, number 22]