BRCT domains: A little more than kin, and less than kind

Abstract

BRCT domains are versatile protein modular domains found as single units or as multiple copies in more than 20 different proteins in the human genome. Interestingly, most BRCT-containing proteins function in the same biological process, the DNA damage response network, but show specificity in their molecular interactions. BRCT domains have been found to bind a wide array of ligands from proteins, phosphorylated linear motifs, and DNA. Here we discuss the biology of BRCT domains and how a domain-centric analysis can aid in the understanding of signal transduction events in the DNA damage response network.

Figure 1. The localization space of BRCT domain-containing proteins

Gene Ontology terms describing the cellular component associated with each of the indicated BRCT domain containing proteins were extracted from the GOA database (http://www.ebi.ac.uk/GOA/). A. Four predominant terms (chromosome, nucleus, cytoplasm, and plasma membrane) were used to generalize the localization space overlap between the indicated tBRCT domain containing proteins, left panel, and their assignments to each of the selected terms, right panel. B. Assignment to each of the cellular component GO terms was used to cluster the BRCT domain containing proteins using PermutMatrix with McQuitty’s criteria for the linkage rule. Yellow indicates an assignment of the GO term, black indicates no association with the GO term.

Figure 2. Backbone and surfaces of crystallized human tandem BRCT domains

A. Backbone ribbon diagrams (colored from blue (N-terminus) to red (C-terminus). B. Electrostatic potential (from red: −7 kT/e to blue: +7 kT/e) mapped onto solvent-accessible surfaces. Graphics produced with PyMOL (Molecular Graphics System, Version 1.3, Schrödinger, LLC) and APBS Tools2 (Lerner MG, Carlson HA (2006) APBS plugin for PyMOL. Ann Arbor, MI: University of Michigan). Information about PDB accession codes and chain identifiers is provided in the text.

Figure 3. Identification of sites in the tandem BRCT under purifying (negative) selection

Solvent-accessible surface of a representative structure (of the C-terminal human BRCA1 fragment) highlighting potentially negatively selected sites. Side-chain atoms shown in black are of amino acids whose codons show signs of having evolved under negative selection. They were computed with the Selecton server [72] across the entire alignment (see text, and Supplementary Materials) based on a taxonomy-based phylogenetic tree for orthologous groups (not shown). “Top” and “Bottom” views are by reference to the orientation used in Figure 2, i.e. the phospho-binding pocket is on the top. Note that the MCPH1 BRCTs were excluded from this analysis because complete coding sequences from elephant and opossum could not be extracted (most likely due to incompleteness of their draft genomes).