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The SMN structure reveals its crucial role in snRNP assembly.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2015 Apr 15; Vol. 24 (8), pp. 2138-46. Date of Electronic Publication: 2015 Jan 05. - Publication Year :
- 2015
-
Abstract
- The spliceosome plays a fundamental role in RNA metabolism by facilitating pre-RNA splicing. To understand how this essential complex is formed, we have used protein crystallography to determine the first complete structures of the key assembler protein, SMN, and the truncated isoform, SMNΔ7, which is found in patients with the disease spinal muscular atrophy (SMA). Comparison of the structures of SMN and SMNΔ7 shows many similar features, including the presence of two Tudor domains, but significant differences are observed in the C-terminal domain, including 12 additional amino acid residues encoded by exon 7 in SMN compared with SMNΔ7. Mapping of missense point mutations found in some SMA patients reveals clustering around three spatial locations, with the largest cluster found in the C-terminal domain. We propose a structural model of SMN binding with the Gemin2 protein and a heptameric Sm ring, revealing a critical assembly role of the residues 260-294, with the differences at the C-terminus of SMNΔ7 compared with SMN likely leading to loss of small nuclear ribonucleoprotein (snRNP) assembly. The SMN complex is proposed to form a dimer driven by formation of a glycine zipper involving α helix formed by amino acid residues 263-294. These results explain how structural changes of SMN give rise to loss of SMN-mediated snRNP assembly and support the hypothesis that this loss results in atrophy of neurons in SMA.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Amino Acid Motifs
Dimerization
Humans
Models, Molecular
Multiprotein Complexes chemistry
Multiprotein Complexes genetics
Multiprotein Complexes metabolism
Muscular Atrophy, Spinal genetics
Mutant Proteins chemistry
Mutant Proteins genetics
Mutant Proteins metabolism
Mutation, Missense
Ribonucleoproteins, Small Nuclear genetics
SMN Complex Proteins genetics
SMN Complex Proteins metabolism
Survival of Motor Neuron 2 Protein chemistry
Survival of Motor Neuron 2 Protein genetics
Survival of Motor Neuron 2 Protein metabolism
Muscular Atrophy, Spinal metabolism
Ribonucleoproteins, Small Nuclear metabolism
SMN Complex Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 24
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25561692
- Full Text :
- https://doi.org/10.1093/hmg/ddu734