Polybromo-1: the chromatin targeting subunit of the PBAF complex

Abstract

The human Polybromo-1 protein (Pb1) was recently identified as a unique subunit of the PBAF (Polybromo, Brg1-Associated Factors) chromatin-remodeling complex required for kinetochore localization during mitosis and the transcription of estrogen-responsive genes. Pb1 coordinates key features common to all remodeling complexes, including chromatin localization, recruitment of protein subunits and alteration of chromatin architecture. A comprehensive analysis of individual domains composing Pb1 is used to propose new information regarding the function of Pb1 in the PBAF chromatin-remodeling complex. The newly identified regulatory role of this important protein is also examined to explain both native function and the emerging role of Pb1 as a tumor suppressor found to be mutated in breast cancer.

Fig. 1

Schematic representation of human Polybromo-1 domain organization. Known and predicted domains for Pb1 are compared to polybromo proteins from the indicated organisms and the homologous yeast Rsc proteins. The proteins shown here share similar domain organization of bromodomains (BrD), bromo-adjacent homology domains (BAH), and the high-mobility group (HMG). Partial domains are indicated.

Fig. 2

Sequence alignments of Pb1 bromodomains. (A) Bromodomain 1 (the amino-terminal bromodomain) for the indicated species from amino acids 45-155 are compared. (B) Bromodomains from Pb1 and Rsc are compared to those with known structures. Highly homologous amino acids based on identity or chemical features (i.e. hydrophobicity or charge) are shown in bold. Annotation of secondary structural elements is based on the structure of the fifth bromodomain (BrD5) of mouse polybromo protein (PDB ID: 2YQD). ClustalW was used to perform the alignment.

Fig. 3

Sequence alignment comparing BAH domains from human and yeast proteins. Highly homologous amino acids based on identity or chemical properties are shown in bold. Annotation of secondary structural elements is based on the structure of the first BAH domain from the chicken polybromo protein (PDB ID: 1W4S). ClustalW was used to perform the alignment.

Fig. 4

Sequence alignment comparing the Pb1 HMG-box with proteins from other organisms. Native sequence or PDB ID is shown in parenthesis. Highly homologous amino acids based on identity or chemical features (i.e. hydrophobicity or charge) are shown in bold. Annotation of secondary structural elements is based on the structure of the HMG domain from mouse HMGX2 (PDB ID: 2CRJ). ClustalW was used to perform the alignment.

Fig. 5

Schematic representation of variations in domain organization for Pb1 isoforms. The HCC1143 mutation of the PB1 gene, as observed in breast tumors, is shown for comparison.