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The structural basis for the oligomerization of the N-terminal domain of SATB1.

Wang Z, Yang X, Chu X, Zhang J, Zhou H, Shen Y, Long J - Nucleic Acids Res. (2012)

Bottom Line: Our results also reveal that SATB1 can form a tetramer through its N-terminal domain.Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets.Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.

ABSTRACT
Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

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Structure of the SATB1 ULD. (A) Schematic representation of the domain organization of mouse SATB1. The ULD domain boundary identified in this work is located from Gly71 to Ser172, and a novel CUTL domain is located from His186 to Lys244. The two mutants used in this study, KWN–AAA and EFH–AAA, were created by substituting the 136K137W138N and the 97E98F162H motifs with ‘AAA’ cassettes. (B) Cartoon representation of the overall structure of ULD. The N- and C-termini of the protein are labeled. (C) Stereo view showing the superimposed structures of ULD and ubiquitin (PDB code: 1UBI).
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gkr1284-F1: Structure of the SATB1 ULD. (A) Schematic representation of the domain organization of mouse SATB1. The ULD domain boundary identified in this work is located from Gly71 to Ser172, and a novel CUTL domain is located from His186 to Lys244. The two mutants used in this study, KWN–AAA and EFH–AAA, were created by substituting the 136K137W138N and the 97E98F162H motifs with ‘AAA’ cassettes. (B) Cartoon representation of the overall structure of ULD. The N- and C-termini of the protein are labeled. (C) Stereo view showing the superimposed structures of ULD and ubiquitin (PDB code: 1UBI).

Mentions: SATB1 was initially identified as a cell type-specific MAR DNA-binding protein, predominantly expressed in the thymus (3). SATB1 consists of an N-terminal domain, a C-terminal homeodomain (HD) and tandem CUT domains in the center (Figure 1A). The sequence-specific binding of SATB1 to its DNA targets is mediated by the HD and CUT tandem domains (13,14) and requires oligomerization of the N-terminal domain (15,16). In addition, chemical interference assays suggested a rapid association and dissociation kinetics of DNA binding by SATB1, and the dissociation rate (Koff) for the multiple AT-rich-containing DNA fragments (such as seven repeats) is slower than the less AT-rich-containing DNA fragments (such as two repeats) (3). In addition to its DNA-binding ability, SATB1 also acts as a ‘docking site’ for various chromatin remodeling/modifying enzymes and transcription factors (5,7,9,11,17). The transcriptional activity of SATB1 is regulated by several post-translational modifications such as phosphorylation (18), acetylation (7,18) and sumoylation (19). Taken together, these studies demonstrate that SATB1 acts as a linker between DNA loop organization, chromatin modification/remodeling and the association of transcription factors with MARs, and thus it functions as a ‘genome organizer’ that is essential for T-cell development (17,20).Figure 1.


The structural basis for the oligomerization of the N-terminal domain of SATB1.

Wang Z, Yang X, Chu X, Zhang J, Zhou H, Shen Y, Long J - Nucleic Acids Res. (2012)

Structure of the SATB1 ULD. (A) Schematic representation of the domain organization of mouse SATB1. The ULD domain boundary identified in this work is located from Gly71 to Ser172, and a novel CUTL domain is located from His186 to Lys244. The two mutants used in this study, KWN–AAA and EFH–AAA, were created by substituting the 136K137W138N and the 97E98F162H motifs with ‘AAA’ cassettes. (B) Cartoon representation of the overall structure of ULD. The N- and C-termini of the protein are labeled. (C) Stereo view showing the superimposed structures of ULD and ubiquitin (PDB code: 1UBI).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351170&req=5

gkr1284-F1: Structure of the SATB1 ULD. (A) Schematic representation of the domain organization of mouse SATB1. The ULD domain boundary identified in this work is located from Gly71 to Ser172, and a novel CUTL domain is located from His186 to Lys244. The two mutants used in this study, KWN–AAA and EFH–AAA, were created by substituting the 136K137W138N and the 97E98F162H motifs with ‘AAA’ cassettes. (B) Cartoon representation of the overall structure of ULD. The N- and C-termini of the protein are labeled. (C) Stereo view showing the superimposed structures of ULD and ubiquitin (PDB code: 1UBI).
Mentions: SATB1 was initially identified as a cell type-specific MAR DNA-binding protein, predominantly expressed in the thymus (3). SATB1 consists of an N-terminal domain, a C-terminal homeodomain (HD) and tandem CUT domains in the center (Figure 1A). The sequence-specific binding of SATB1 to its DNA targets is mediated by the HD and CUT tandem domains (13,14) and requires oligomerization of the N-terminal domain (15,16). In addition, chemical interference assays suggested a rapid association and dissociation kinetics of DNA binding by SATB1, and the dissociation rate (Koff) for the multiple AT-rich-containing DNA fragments (such as seven repeats) is slower than the less AT-rich-containing DNA fragments (such as two repeats) (3). In addition to its DNA-binding ability, SATB1 also acts as a ‘docking site’ for various chromatin remodeling/modifying enzymes and transcription factors (5,7,9,11,17). The transcriptional activity of SATB1 is regulated by several post-translational modifications such as phosphorylation (18), acetylation (7,18) and sumoylation (19). Taken together, these studies demonstrate that SATB1 acts as a linker between DNA loop organization, chromatin modification/remodeling and the association of transcription factors with MARs, and thus it functions as a ‘genome organizer’ that is essential for T-cell development (17,20).Figure 1.

Bottom Line: Our results also reveal that SATB1 can form a tetramer through its N-terminal domain.Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets.Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.

ABSTRACT
Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

Show MeSH
Related in: MedlinePlus