MBT domain proteins in development and disease

Abstract

The Malignant Brain Tumor (MBT) domain is a "chromatin reader", a protein module that binds to post-translational modifications on histone tails that are thought to affect a variety of chromatin processes, including transcription. More specifically, MBT domains recognize mono- and di-methylated lysines at a number of different positions on histone H3 and H4 tails. Three Drosophila proteins, SCM, L(3)MBT and SFMBT contain multiple adjacent MBT repeats and have critical roles in development, maintenance of cell identity, and tumor suppression. Although they function in different pathways, these proteins all localize to chromatin in vivo and repress transcription by a currently unknown molecular mechanism that requires the MBT domains. The human genome contains several homologues of these MBT proteins, some of which have been linked to important gene regulatory pathways, such as E2F/Rb- and Polycomb-mediated repression, and to the insurgence of certain neurological tumors. Here, we review the genetics, biochemistry, and cell biology of MBT proteins and their role in development and disease.

Figure 1. Evolutionary relationship and domain organization of MBT proteins

On the left, the putative evolutionary relationship between MBT containing proteins is shown in a cladogram, based on primary sequence similarity. All known MBT proteins in the C. elegans D. melanogaster, and H. sapiens genomes are indicated. On the right a schematic representation of domain organization in the same MBT proteins is shown. The different conserved domains are color-coded according to the legend. When known, the MBT repeat that binds to histone tails is indicated with a yellow asterisk.

Figure 2. Structural features of the MBT repeats

(A) The crystal structure of the 2^nd MBT repeat of hL3MBTL is shown in complex with the ligand H4K20me2 (left) and compared with a similar structure obtained for the chromodomain of dHP1 in complex with H3K9me3 (right). The two different modes of binding, pocket insertion versus surface groove are illustrated. Figures were generated with UCSF chimera and POV raytracing software using atomic coordinates from PDB entries 2PQW and 1Q3L. Surface colors indicate hydrophobicity according to the Kyte-Doolittle scale, ranging from blue for the most hydrophilic to red for the most hydrophobic. (B) Schematic depiction of higher order organization of 2, 3, and 4 tandem MBT repeats, as found in SCM, L(3)MBT and SFMBT family proteins. Structurally homologous domains across families are in the same color. Known binding sites for histone peptides are marked with an arrow. The atomic coordinates used were from PDB entries 2R5A, 1OZ2 and 3F70.

Figure 3. Recruitment and function of MBT proteins

Putative mechanisms for the recruitment of MBT proteins to chromatin (left) and their repressive effect on transcription (right) are schematized. See text for details.