Siew Choo Lim1,2, Matthew W. Bowler3, Ting Feng Lai1,2 and Haiwei Song1,4,5.
1- Institute of Molecular and Cell Biology, Proteos, Singapore 138673
2- School of Biological Sciences, Nanyang Technological University, Singapore 637551
3- Structural Biology Group, European Synchrotron Radiation Facility, F-38043 Grenoble, France
4- Life Sciences Institute, Zhejiang University, Hangzhou, China
5- Department of Biochemistry, National University of Singapore, Singapore 117543
Published online in Nucl. Acids Res. on 10 September 2012. [Epub ahead of print]
Mutations in immunoglobulin µ-binding protein 2 (Ighmbp2) cause distal spinal muscular atrophy type 1 (DSMA1), an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. However, despite extensive studies, the mechanism of disease-causing mutations remains elusive. Here we report the crystal structures of the Ighmbp2 helicase core with and without bound RNA. The structures show that the overall fold of Ighmbp2 is very similar to that of Upf1, a key helicase involved in nonsense-mediated mRNA decay. Similar to Upf1, domains 1B and 1C of Ighmbp2 undergo large conformational changes in response to RNA binding, rotating 30° and 10°, respectively. The RNA binding and ATPase activities of Ighmbp2 are further enhanced by the R3H domain, located just downstream of the helicase core. Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure provides a molecular basis for understanding the disease-causing consequences of Ighmbp2 mutations.
Structural overview of hIghmbp2hd and hIghmbp2hd–RNA. (A) Schematic representation of the domain arrangement in Upf1 and Ighmbp2. The helicase core region contains two RecA-like domains: domain 1A (pink) and domain 2A (wheat) and additional regulatory domains: domain 1B (green), domain 1C (cyan) and the ‘stalk’ (orange). Upf1 contains another regulatory domain, the CH domain (gray) located upstream of the helicase region while Ighmbp2 features two more another regulatory domains: a R3H domain (gray) and an AN-1 type zinc-finger domain (gray) downstream of the helicase region. Missense mutations and canonical motifs in Ighmbp2 are labeled. (B) Crystal structures of hIghmbp2hd. (C) Crystal structure of hIghmbp2hd–RNA. The coloring schemes for domains are as in (A). The bound phosphate ion and ssRNA are shown as red sphere and yellow cartoon tube, respectively.
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