Nucleic Acids Research Advance Access originally published online on August 28, 2007
Nucleic Acids Research 2007 35(17):5913-5921; doi:10.1093/nar/gkm626
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Nucleic Acids Research, 2007, Vol. 35, No. 17 5913-5921
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Molecular basis of Diamond–Blackfan anemia: structure and function analysis of RPS19
1INSERM U869, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit Pessac, F-33607, 2Université Victor Segalen, Bordeaux 2, F-33076, 3Laboratoire de Biologie Moléculaire des eucaryotes (UMR5099) and Institut d’Exploration Fonctionnelle des Génomes (IFR109), CNRS and Université Paul Sabatier, 118 route de Narbonne F-31062 Toulouse and 4Synchrotron SOLEIL L’Orme des Merisiers, Saint Aubin- BP48, 91192 Gif sur Yvette Cedex, France
*To whom correspondence should be addressed. Tel: 00 33 5 40 00 30 63; Fax: 00 33 5 40 00 30 68; Email: s.fribourg{at}iecb.u-bordeaux.fr Correspondence may also be addressed to Pierre-Emmanuel Gleizes. Tel/Fax: 00 33 5 61 33 59 26/58 86, Email: gleizes{at}ibcg.biotoul.fr
Received July 6, 2007. Revised July 30, 2007. Accepted July 30, 2007.
Diamond–Blackfan anemia (DBA) is a rare congenital disease linked to mutations in the ribosomal protein genes rps19, rps24 and rps17. It belongs to the emerging class of ribosomal disorders. To understand the impact of DBA mutations on RPS19 function, we have solved the crystal structure of RPS19 from Pyrococcus abyssi. The protein forms a five 
-helix bundle organized around a central amphipathic -helix, which corresponds to the DBA mutation hot spot. From the structure, we classify DBA mutations relative to their respective impact on protein folding (class I) or on surface properties (class II). Class II mutations cluster into two conserved basic patches. In vivo analysis in yeast demonstrates an essential role for class II residues in the incorporation into pre-40S ribosomal particles. This data indicate that missense mutations in DBA primarily affect the capacity of the protein to be incorporated into pre-ribosomes, thus blocking maturation of the pre-40S particles.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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