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 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.
Bibliographical noteFunding Information:
We thank Corie Ralston and Christy Bertoldo for their assistance with X-ray data collection at the Advanced Light Source (ALS, Berkeley, CA) synchrotron beamlines 8.2.1 and 8.2.2. We thank Emily Anna Bridges for help with bacterial cell culture. We are grateful to the members of our laboratory for helpful discussions and comments on this manuscript. This work was supported by the Association Française Contre les Myopathies. G.D. is an Investigator of the Howard Hughes Medical Institute.