The structure of Sif2p, a WD repeat protein functioning in the SET3 corepressor complex

Area of Science:

• Molecular Biology
• Structural Biology
• Yeast Genetics

Background:

• The Set3 complex (SET3C) in Saccharomyces cerevisiae is homologous to human SMRT and N-CoR corepressor complexes.
• SET3C possesses histone deacetylase activity, regulating meiotic gene expression.
• SIF2 encodes Sif2p, a core protein within the SET3C.

Purpose of the Study:

• To determine the X-ray crystal structure of a key domain of the yeast Sif2p protein.
• To investigate the oligomeric state and interaction domains of Sif2p.
• To compare Sif2p structure and function with homologous human proteins.

Main Methods:

• X-ray crystallography was used to determine the structure of the Sif2p C-terminal domain at 1.55 Å resolution.
• Analytical ultracentrifugation or similar methods were used to assess the oligomeric state of intact Sif2p.
• Protein interaction studies mapped the role of the N-terminal LisH domain.
• Multiple sequence alignments were performed to identify conserved regions.

Main Results:

• The C-terminal domain of Sif2p adopts an unusual eight-bladed beta-propeller fold.
• This structure differs from seven-bladed beta-propellers found in other corepressors like Tup1p and Groucho.
• Intact Sif2p exists as a tetramer, mediated by its N-terminal LisH domain.
• The LisH domain also mediates interaction with Snt1p, another SET3C component.
• A conserved surface on the beta-propeller suggests a common protein-binding interface.

Conclusions:

• Sif2p possesses a unique structural fold within the transcriptional corepressor family.
• Its tetrameric structure and interaction domains are critical for SET3C assembly and function.
• Sif2p is likely the yeast homolog of human TBL1/TBLR1, implying conserved structural and functional roles in N-CoR/SMRT complexes.