Structure of a Key Intermediate of the SMN Complex Reveals Gemin2's Crucial Function in snRNP Assembly

• Published in: Cell Vol. 146; no. 3; pp. 384 - 395
• Main Authors: Zhang, Rundong, So, Byung Ran, Li, Pilong, Yong, Jeongsik, Glisovic, Tina, Wan, Lili, Dreyfuss, Gideon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2011
• Subjects: Amino Acid Sequence; Animals; biogenesis; crystal structure; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Sequence Data; muscular atrophy; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; pathogenesis; proteins; Ribonucleoproteins, Small Nuclear - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sequence Alignment; small nuclear RNA; SMN Complex Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.06.043

The SMN complex mediates the assembly of heptameric Sm protein rings on small nuclear RNAs (snRNAs), which are essential for snRNP function. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing subunits, respectively. The mechanism by which the Sm proteins are gathered while preventing illicit Sm assembly on non-snRNAs is unknown. Here, we describe the 2.5 Å crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN's Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins, and gripping its bottom and top sides and outer perimeter. Gemin2 reaches into the RNA-binding pocket, preventing RNA binding. Interestingly, SMN-Gemin2 interaction is abrogated by a spinal muscular atrophy (SMA)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide insight into SMN complex assembly and specificity, linking snRNP biogenesis and SMA pathogenesis. [Display omitted] ► Gemin2 binds five Sm proteins and SMN for snRNPs' heptameric Sm core biogenesis ► Assembly intermediate structure shows Gemin2 grips Sm pentamer, bridging to SMN ► Gemin2 blocks RNA-binding pocket preventing illicit Sm core assembly ► SMN-Gemin2 interaction is abrogated by a spinal muscular atrophy-causing mutation