Molecular Architecture of SF3b and Structural Consequences of Its Cancer-Related Mutations
Models, Molecular
Oncogene Proteins
Protein Conformation, alpha-Helical
0301 basic medicine
0303 health sciences
Binding Sites
Gene Expression
Moths
Crystallography, X-Ray
Phosphoproteins
Neoplasm Proteins
3. Good health
03 medical and health sciences
Mutation
Animals
Humans
Genes, Tumor Suppressor
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Amino Acid Sequence
Cloning, Molecular
Baculoviridae
HeLa Cells
Protein Binding
DOI:
10.1016/j.molcel.2016.08.036
Publication Date:
2016-10-10T03:16:20Z
AUTHORS (10)
ABSTRACT
SF3b is a heptameric protein complex of the U2 small nuclear ribonucleoprotein (snRNP) that is essential for pre-mRNA splicing. Mutations in the largest SF3b subunit, SF3B1/SF3b155, are linked to cancer and lead to alternative branch site (BS) selection. Here we report the crystal structure of a human SF3b core complex, revealing how the distinctive conformation of SF3b155's HEAT domain is maintained by multiple contacts with SF3b130, SF3b10, and SF3b14b. Protein-protein crosslinking enabled the localization of the BS-binding proteins p14 and U2AF65 within SF3b155's HEAT-repeat superhelix, which together with SF3b14b forms a composite RNA-binding platform. SF3b155 residues, the mutation of which leads to cancer, contribute to the tertiary structure of the HEAT superhelix and its surface properties in the proximity of p14 and U2AF65. The molecular architecture of SF3b reveals the spatial organization of cancer-related SF3b155 mutations and advances our understanding of their effects on SF3b structure and function.
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