Human Molecular Genetics, 2002, Vol. 11, No. 15 1785-1795
© 2002 Oxford University Press
SMN, the spinal muscular atrophy protein, forms a pre-import snRNP complex with snurportin1 and importin ß
Department of Genetics, Center for Human Genetics and Program in Cell Biology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA
Received April 16, 2002; Accepted May 16, 2002
The survival of motor neuron (SMN) protein is mutated in patients with spinal muscular atrophy (SMA). SMN is part of a multiprotein complex required for biogenesis of the Sm class of small nuclear ribonucleoproteins (snRNPs). Following assembly of the Sm core domain, snRNPs are transported to the nucleus via importin ß. Sm snRNPs contain a nuclear localization signal (NLS) consisting of a 2,2,7-trimethylguanosine (TMG) cap and the Sm core. Snurportin1 (SPN) is the adaptor protein that recognizes both the TMG cap and importin ß. Here, we report that a mutant SPN construct lacking the importin ß binding domain (IBB), but containing an intact TMG cap-binding domain, localizes primarily to the nucleus, whereas full-length SPN localizes to the cytoplasm. The nuclear localization of the mutant SPN was not a result of passive diffusion through the nuclear pores. Importantly, we found that SPN interacts with SMN, Gemin3, Sm snRNPs and importin ß. In the presence of ribonucleases, the interactions with SMN and Sm proteins were abolished, indicating that snRNAs mediate this interplay. Cell fractionation studies showed that SPN binds preferentially to cytoplasmic SMN complexes. Notably, we found that SMN directly interacts with importin ß in a GST-pulldown assay, suggesting that the SMN complex might represent the Sm core NLS receptor predicted by previous studies. Therefore, we conclude that, following Sm protein assembly, the SMN complex persists until the final stages of cytoplasmic snRNP maturation and may provide somatic cell RNPs with an alternative NLS.
* To whom correspondence should be addressed at: Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA. Tel: +1 2163684922; Fax: +1 2163683432; Email: gxm26{at}po.cwru.edu
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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