Human bromodomain containing protein 3

From Proteopedia

An SGC Structure

BRD3: Human bromodomain containing protein 3 (domains 1 and 2)

PDB Code: 2nxb and 2oo1

2nxb: Filippakopoulos, P., Bullock, A., Cooper, C., Keates, K., Berridge, G., Pike, A., Bunkoczi, G., Gileadi, O., Lee, W.H., Muller, S., Marsden, B.D., Sundstrom, M., von Delft, F., Knapp, S.

2oo1: Filippakopoulos, P., Bullock, A., Papagrigoriou, E., Keates, T., Cooper, C., Smee, C., Ugochukwu, E., Debreczeni, J., Gileadi, O., von Delft, F., Lee, W.H., Muller, S., Marsden, B.D., Sundstrom, M., Knapp, S.

Description

BRD3 belongs to the BET subclass of proteins, which are distinguished by two N-terminal bromodomains and one ET (Extra Terminal) domain. BRDs have been found to be associated with chromatin. The poorly characterized ET domain functions as a protein-protein interaction motif and may be part of an atypical serine-kinase activity. The subclass consists of at least four members in mouse and human, Brd2 (also referred to as Fsrg1, RING3), Brd3(Fsrg2, ORFX), Brd4 (Fsrg4, MCAP/HUNK1), and Brdt (Fsrg3, BRD6). BRD proteins are related to the female sterile homeotic protein gene in Drosophila, a gene required maternally for proper expression of other homeotic genes, such as Ubx, which is involved in pattern formation. BRD3 mRNA is ubiquitously expressed in human adult and fetal tissues with highest expression in testis, ovary, placenta, uterus, and brain. BRD3 expression is induced in activated lymphocytes and it is highly expressed in undifferentiated ES cells whereas expression levels are reduced upon endothelial differentiation.

Down regulated expression or loss of BRD3 has been detected in biopsies of nasopharyngeal carcinomas and altered expression levels have been found in bladder cancer. In addition, the BRD3 gene is located to chromosome 9q34, a region susceptible to genomic rearrangement in tumors. BRD3 has also been proposed as a marker for hormone dependent cancer. BRD3 also interacts with LANA-1, the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen 1, which is required for the replication of episomal viral genomes. Here we report the structure of the first and second individual bromodomains of BRD3.

Structural features

The structures of BRD3 discussed here comprises two independent structures of the first bromo domain (BD1) including the sequence between residue Glu25 and Glu144 as well as the second bromo domain (BD2) (residues Lys307-Pro416). The of BD1 contains two protein molecules in addition to one sodium ion and 7 ethylene glycole molecules used as a cryo protecting agent. Both BD1 molecules present in the asymmetric unit with an r.m.s.d. of ~1Å. The main structural differences are located in the large loop region connecting helix 1 with helix 2 (Asp64-Lys78) which is involved in the binding of acetylated lysine containing sequences. The N-terminal residues Glu25-Gly333 were only visible in chain A.

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The interface between both BRD3 BD1 monomers covers a large mainly hydrophobic surface area suggesting that this domain might be dimeric in solution. Dimerization of bromo domains has also been suggested for the closely related protein BRD2. However, the interface which is formed in BRD2 by the two C-terminal helices is not conserved in BRD3. As expected from their high degrees of sequence conservation (78% identity) the overall fold of BRD3 is closely related to the bromo domain of BRD2 (r.m.s.d 0.7 Å between chain B BRD3 and chain A BRD2; pdb-code: 1x0j).

The asymmetric unit of BRD3 BD2 contains 4 protein molecules, 2 sodium ions as well as a number of ethylene glycole molecules. Also in this case, the putative dimmer interface is different to the one observed in BRD2. The interface between BRD3 BD2 is mainly governed by a few hydrophilic interactions making it not likely that this molecule is dimeric in solution.

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References

• Boyer A, Lussier JG, Sinclair AH, McClive PJ, Silversides DW. Pre-sertoli specific gene expression profiling reveals differential expression of Ppt1 and Brd3 genes within the mouse genital ridge at the time of sex determination. Biol Reprod. 2004 Sep;71(3):820-7. Epub 2004 May 5. PMID:15128596 doi:10.1095/biolreprod.104.029371
• Ishii H, Mimori K, Mori M, Vecchione A. Differentially expressed genes in endothelial differentiation. DNA Cell Biol. 2005 Jul;24(7):432-7. PMID:16008511 doi:10.1089/dna.2005.24.432
• Ottinger M, Christalla T, Nathan K, Brinkmann MM, Viejo-Borbolla A, Schulz TF. Kaposi's sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-induced G1 cell cycle arrest. J Virol. 2006 Nov;80(21):10772-86. Epub 2006 Aug 23. PMID:16928766 doi:10.1128/JVI.00804-06
• Thorpe KL, Gorman P, Thomas C, Sheer D, Trowsdale J, Beck S. Chromosomal localization, gene structure and transcription pattern of the ORFX gene, a homologue of the MHC-linked RING3 gene. Gene. 1997 Oct 24;200(1-2):177-83. PMID:9373153
• Zhou M, Peng C, Nie XM, Zhang BC, Zhu SG, Yu Y, Li XL, Li GY. [Expression of BRD7-interacting proteins,BRD2 and BRD3, in nasopharyngeal carcinoma tissues] Ai Zheng. 2003 Feb;22(2):123-7. PMID:12600283