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Insights into association of the NuRD complex with FOG-1 from the crystal structure of an RbAp48·FOG-1 complex.

Lejon S, Thong SY, Murthy A, AlQarni S, Murzina NV, Blobel GA, Laue ED, Mackay JP - J. Biol. Chem. (2010)

Bottom Line: The FOG-1 peptide contacts a negatively charged binding pocket on top of the RbAp48 β-propeller that is distinct from the binding surface used by RpAp48 to contact histone H4.We further show that RbAp48 interacts with the NuRD subunit MTA-1 via a surface that is distinct from its FOG-binding pocket, providing a first glimpse into the way in which NuRD assembly facilitates interactions with cofactors.Our RbAp48·FOG-1 structure provides insight into the molecular determinants of FOG-1-dependent association with the NuRD complex and into the links between transcription regulation and nucleosome remodeling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.

ABSTRACT
Chromatin-modifying complexes such as the NuRD complex are recruited to particular genomic sites by gene-specific nuclear factors. Overall, however, little is known about the molecular basis for these interactions. Here, we present the 1.9 Å resolution crystal structure of the NuRD subunit RbAp48 bound to the 15 N-terminal amino acids of the GATA-1 cofactor FOG-1. The FOG-1 peptide contacts a negatively charged binding pocket on top of the RbAp48 β-propeller that is distinct from the binding surface used by RpAp48 to contact histone H4. We further show that RbAp48 interacts with the NuRD subunit MTA-1 via a surface that is distinct from its FOG-binding pocket, providing a first glimpse into the way in which NuRD assembly facilitates interactions with cofactors. Our RbAp48·FOG-1 structure provides insight into the molecular determinants of FOG-1-dependent association with the NuRD complex and into the links between transcription regulation and nucleosome remodeling.

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Sequence alignment of the 12 N-terminal residues of human FOG-1, FOG-2, CTIP1 (BC11A), CTIP2 (BC11B), and SALL1 and murine EBFAZ. The consensus sequence is shown below the alignment.
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Figure 6: Sequence alignment of the 12 N-terminal residues of human FOG-1, FOG-2, CTIP1 (BC11A), CTIP2 (BC11B), and SALL1 and murine EBFAZ. The consensus sequence is shown below the alignment.

Mentions: A sequence alignment of human proteins known to contain the N-terminal RRKQXXP motif is shown in Fig. 6. The general conservation of this motif in several co-repressors and transcription factors, including the transcription factor SALL1 (38), EBFAZ (early B-cell factor-associated zinc finger protein), and the B-cell leukemia/lymphoma proteins BC11A and BC11B (also known as CTIP1 and CTIP2 (C-terminal binding protein-interacting protein), respectively), suggests that they are likely to recruit the NuRD complex in a similar manner. The structure of FOG-1-(1–15) bound to RbAp48 described here underscores the dependence of the binding on the RRKQ submotif, as the majority of the specific interactions are conferred by these residues. In particular, FOG-1 residues Arg-3, Arg-4, and Lys-5 have been found to be important for the interaction, as mutation in any one of these positions results in the loss of NuRD binding and GATA-1-mediated repression (27, 39). Consistent with these data, the side chains of the two non-conserved residues immediately following the RRKQ submotif (Ser and Asn in FOG-1) are not engaged in interactions with RbAp48 but are instead oriented toward the solvent.


Insights into association of the NuRD complex with FOG-1 from the crystal structure of an RbAp48·FOG-1 complex.

Lejon S, Thong SY, Murthy A, AlQarni S, Murzina NV, Blobel GA, Laue ED, Mackay JP - J. Biol. Chem. (2010)

Sequence alignment of the 12 N-terminal residues of human FOG-1, FOG-2, CTIP1 (BC11A), CTIP2 (BC11B), and SALL1 and murine EBFAZ. The consensus sequence is shown below the alignment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3020727&req=5

Figure 6: Sequence alignment of the 12 N-terminal residues of human FOG-1, FOG-2, CTIP1 (BC11A), CTIP2 (BC11B), and SALL1 and murine EBFAZ. The consensus sequence is shown below the alignment.
Mentions: A sequence alignment of human proteins known to contain the N-terminal RRKQXXP motif is shown in Fig. 6. The general conservation of this motif in several co-repressors and transcription factors, including the transcription factor SALL1 (38), EBFAZ (early B-cell factor-associated zinc finger protein), and the B-cell leukemia/lymphoma proteins BC11A and BC11B (also known as CTIP1 and CTIP2 (C-terminal binding protein-interacting protein), respectively), suggests that they are likely to recruit the NuRD complex in a similar manner. The structure of FOG-1-(1–15) bound to RbAp48 described here underscores the dependence of the binding on the RRKQ submotif, as the majority of the specific interactions are conferred by these residues. In particular, FOG-1 residues Arg-3, Arg-4, and Lys-5 have been found to be important for the interaction, as mutation in any one of these positions results in the loss of NuRD binding and GATA-1-mediated repression (27, 39). Consistent with these data, the side chains of the two non-conserved residues immediately following the RRKQ submotif (Ser and Asn in FOG-1) are not engaged in interactions with RbAp48 but are instead oriented toward the solvent.

Bottom Line: The FOG-1 peptide contacts a negatively charged binding pocket on top of the RbAp48 β-propeller that is distinct from the binding surface used by RpAp48 to contact histone H4.We further show that RbAp48 interacts with the NuRD subunit MTA-1 via a surface that is distinct from its FOG-binding pocket, providing a first glimpse into the way in which NuRD assembly facilitates interactions with cofactors.Our RbAp48·FOG-1 structure provides insight into the molecular determinants of FOG-1-dependent association with the NuRD complex and into the links between transcription regulation and nucleosome remodeling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.

ABSTRACT
Chromatin-modifying complexes such as the NuRD complex are recruited to particular genomic sites by gene-specific nuclear factors. Overall, however, little is known about the molecular basis for these interactions. Here, we present the 1.9 Å resolution crystal structure of the NuRD subunit RbAp48 bound to the 15 N-terminal amino acids of the GATA-1 cofactor FOG-1. The FOG-1 peptide contacts a negatively charged binding pocket on top of the RbAp48 β-propeller that is distinct from the binding surface used by RpAp48 to contact histone H4. We further show that RbAp48 interacts with the NuRD subunit MTA-1 via a surface that is distinct from its FOG-binding pocket, providing a first glimpse into the way in which NuRD assembly facilitates interactions with cofactors. Our RbAp48·FOG-1 structure provides insight into the molecular determinants of FOG-1-dependent association with the NuRD complex and into the links between transcription regulation and nucleosome remodeling.

Show MeSH