To better understand the roles of Sm proteins in forming the cores of many RNA-processing ribonucleoproteins, we determined the crystal structure of an atypical Sm-like archaeal protein (SmAP3) in which the conserved Sm domain is augmented by a previously uncharacterized, mixed ␣͞␤ C-terminal domain. The structure reveals an unexpected SmAP3 14-mer that is perforated by a cylindrical pore and is bound to 14 cadmium (Cd 2؉ ) ions. Individual heptamers adopt either ''apical'' or ''equatorial'' conformations that chelate Cd 2؉ differently. SmAP3 forms supraheptameric oligomers (SmAP3) n ‫؍‬ 7,14,28 in solution, and assembly of the asymmetric 14-mer is modulated by differential divalent cation-binding in apical and equatorial subunits. Phylogenetic and sequence analyses substantiate SmAP3s as a unique subset of SmAPs. These results distinguish SmAP3s from other Sm proteins and provide a model for the structure and properties of Sm proteins >100 residues in length, e.g., several human Sm proteins. S m proteins are key components of the ribonucleoprotein (RNP) assemblies that are required for high-fidelity cellular RNA processing, including rRNA and tRNA processing, mRNA decapping and decay, and intron splicing in pre-mRNA (1). Although the primary functions of Sm⅐⅐⅐RNA interactions in many RNPs are unclear, the importance of Sm proteins is illustrated by their roles in forming the cores of the uridine-rich small nuclear RNPs (U snRNPs) that further assemble into a large, transiently stable spliceosome that catalyzes the final step of eukaryotic pre-mRNA processing (intron excision͞exon ligation; ref. 2). Each spliceosomal snRNP consists of a unique snRNA and up to dozens of snRNPspecific proteins (3). The only subset of proteins common to different snRNPs is the archetypal Sm heteroheptamer (e.g., human Sm D1⅐D2⅐F⅐E⅐G⅐D3⅐B͞BЈ; ref. 4), which assembles snRNP cores by binding to uridine-rich, single-stranded regions of snRNA via discrete intermediates (e.g., D3⅐B, D1⅐D2, and E⅐F⅐G heteromers; ref. 5). Sm proteins also may function as nuclear localization signals and in hypermethylation of snRNA caps (6). Functional complexes of RNA and homologous Sm protein septets, such as the Sm-like (Lsm) 1 3 7 and Lsm 2 3 8 paralogs of yeast, are thought to assemble in a similar manner as canonical Sm proteins (7).The Sm domain is highly conserved across many species, and its widespread phylogenetic distribution suggests its importance in the early evolution of RNA metabolism. Homologs of snRNP core Sm proteins occur in eukaryotes ranging from yeast to human. The existence of Sm-like archaeal proteins (SmAPs) implies an ancient origin of Sm proteins (8-10). Most recently, the Escherichia coli Hfq protein (a host factor required for bacteriophage replication) and its orthologs were shown to be Sm-like proteins in several eubacterial lineages (11), thus expanding the scope of possible Sm-like functions to include nonsplicing roles (12). Organisms may contain from Ϸ1-3 Sm-like proteins (as in archaea) to multiple sets of seven Sm and ...

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