Limits...
Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex.

Hudson GM, Watson PJ, Fairall L, Jamieson AG, Schwabe JW - J. Biol. Chem. (2015)

Bottom Line: The class IIa HDACs are associated with the SMRT/NCoR repression complexes and this may, at least in part, account for their repressive activity.Mutational analysis of HDAC4 suggests that the peptide interacts in the vicinity of the active site of the enzyme and requires the "closed" conformation of the zinc-binding loop on the surface of the enzyme.Together these findings represent the first insights into the molecular mechanism of recruitment of class IIa HDACs to the SMRT/NCoR repression complexes.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN and.

Show MeSH
A repeated sequence motif within the class IIa HDAC binding region of SMRT/NCOR co-repressors.A, domain arrangement of SMRT indicating regions known to interact with partner proteins and schematic of RD3 of SMRT/NCoR showing the location of identified GSI repeats and the BCL6 binding domain with a similar arrangement and spacing. B, Weblogo plot of RD3 GSI motifs from SMRT and NCoR of 6 species demonstrates a well conserved 8 amino acid residue motif. NR, nuclear receptor binding region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4505066&req=5

Figure 1: A repeated sequence motif within the class IIa HDAC binding region of SMRT/NCOR co-repressors.A, domain arrangement of SMRT indicating regions known to interact with partner proteins and schematic of RD3 of SMRT/NCoR showing the location of identified GSI repeats and the BCL6 binding domain with a similar arrangement and spacing. B, Weblogo plot of RD3 GSI motifs from SMRT and NCoR of 6 species demonstrates a well conserved 8 amino acid residue motif. NR, nuclear receptor binding region.

Mentions: The so-called repression domain 3 (RD3) of SMRT and NCoR has previously been shown to interact both with the repressive transcription factor BCL6 and with the class IIa HDACs (16, 21–23). Sequence analysis of the RD3 regions of SMRT and NCoR indicates that these regions are intrinsically unstructured. Strikingly, within the RD3 domain, we observed a repeated 8-amino acid motif with a consensus sequence G-S-I-t/s-q-G-t-P (capitals indicate absolute conservation). In SMRT and NCoR there are 5 and 6 GSI motifs, respectively, with an apparent core conserved region consisting of 4 motifs flanking the BCL6 binding domain (Fig. 1A). Alignment of >70 GSI motifs and the flanking regions from multiple SMRT/NCoR homologues suggests that the sequence conservation is restricted to the core eight amino acids (Fig. 1B) suggesting an important functional role for this motif. Interestingly a scan prosite search using GSI(S/T)XGXP as a search pattern indicates that this motif is not found in any other proteins in the human proteome. We hypothesized therefore that these GSI motifs might play a role in mediating interaction of co-repressor proteins with the class IIa HDACs.


Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex.

Hudson GM, Watson PJ, Fairall L, Jamieson AG, Schwabe JW - J. Biol. Chem. (2015)

A repeated sequence motif within the class IIa HDAC binding region of SMRT/NCOR co-repressors.A, domain arrangement of SMRT indicating regions known to interact with partner proteins and schematic of RD3 of SMRT/NCoR showing the location of identified GSI repeats and the BCL6 binding domain with a similar arrangement and spacing. B, Weblogo plot of RD3 GSI motifs from SMRT and NCoR of 6 species demonstrates a well conserved 8 amino acid residue motif. NR, nuclear receptor binding region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4505066&req=5

Figure 1: A repeated sequence motif within the class IIa HDAC binding region of SMRT/NCOR co-repressors.A, domain arrangement of SMRT indicating regions known to interact with partner proteins and schematic of RD3 of SMRT/NCoR showing the location of identified GSI repeats and the BCL6 binding domain with a similar arrangement and spacing. B, Weblogo plot of RD3 GSI motifs from SMRT and NCoR of 6 species demonstrates a well conserved 8 amino acid residue motif. NR, nuclear receptor binding region.
Mentions: The so-called repression domain 3 (RD3) of SMRT and NCoR has previously been shown to interact both with the repressive transcription factor BCL6 and with the class IIa HDACs (16, 21–23). Sequence analysis of the RD3 regions of SMRT and NCoR indicates that these regions are intrinsically unstructured. Strikingly, within the RD3 domain, we observed a repeated 8-amino acid motif with a consensus sequence G-S-I-t/s-q-G-t-P (capitals indicate absolute conservation). In SMRT and NCoR there are 5 and 6 GSI motifs, respectively, with an apparent core conserved region consisting of 4 motifs flanking the BCL6 binding domain (Fig. 1A). Alignment of >70 GSI motifs and the flanking regions from multiple SMRT/NCoR homologues suggests that the sequence conservation is restricted to the core eight amino acids (Fig. 1B) suggesting an important functional role for this motif. Interestingly a scan prosite search using GSI(S/T)XGXP as a search pattern indicates that this motif is not found in any other proteins in the human proteome. We hypothesized therefore that these GSI motifs might play a role in mediating interaction of co-repressor proteins with the class IIa HDACs.

Bottom Line: The class IIa HDACs are associated with the SMRT/NCoR repression complexes and this may, at least in part, account for their repressive activity.Mutational analysis of HDAC4 suggests that the peptide interacts in the vicinity of the active site of the enzyme and requires the "closed" conformation of the zinc-binding loop on the surface of the enzyme.Together these findings represent the first insights into the molecular mechanism of recruitment of class IIa HDACs to the SMRT/NCoR repression complexes.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 9HN and.

Show MeSH