LIG_PALB2_WD40_1

PALB2 WD40 repeat binding motif in BRCA2

The repair of DNA double-strand breaks and interstrand crosslinks by homologous recombination requires the co-ordinated assembly of several multi-protein complexes. BRCA2 protein plays a central role to this function and its activity is largely affected by a protein known as PALB2. PALB2 acts as a tumor suppressor gene important for localizing BRCA2 to sites of DNA damage (Park,2014). The interactions between these two proteins are mediated by the C-terminal region of PALB2, which contains a WD40 repeat domain, and the N-terminal site of BRCA2 protein. This interface is required for the protein interaction and function as missense mutations in either protein can disrupt the interaction. Also the mutations of these proteins are implicated in a variety of cancers. Mono-allelic germline mutations of BRCA2 and PALB2 are risk alleles of female breast, ovarian and familial pancreatic cancer, while bi-allelic mutations cause a severe form of Fanconi anemia (Park,2014).

The DNA damage repair mechanism is necessary for the maintainance of genome integrity. PALB2 serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination (Zhang,2009). It acts upstream of BRCA2 in the information flow, from recognition of a DNA double-strand break to assembly of the RAD51 nucleoprotein filament. PALB2 independently interacts with BRCA1 and BRCA2 through its NH2 and COOH terminal regions. The C-terminus of PALB2, which contains a seven-bladed WD40-type β-propeller structure, is required for the interaction of PALB2 with BRCA2. The N-terminal motif of the BRCA2 protein binds in a pocket formed by the tips of the fourth and fifth blades on the bottom face of the β-propeller. The core interaction is mediated by the BRCA2 residues W31, F32 and L35 which project from a short helix and bind into a hydrophobic pocket lined by the PALB2 residues (3EU7). The core interaction is augmented by polar interactions, including a water bridge from the indole nitrogen of BRCA2 W31 to S1065 in the wall of the PALB2 pocket. Other interactions N-terminal to the core interaction are mediated by the BRCA2 residues I27 and L29 which bind to the PALB2 residues M1067, G1068 and L1069. Mutation of the hydrophobic core forming residue, A1025 which binds to F32 of BRCA2 completely abolishes the interaction confirming the functional role of the pocket. A single missense mutation in the interaction surface of either protein is sufficient to disrupt the interaction and many of them are associated with cancer (Oliver,2009). The motif pattern in ELM is based solely on the three core residues. The region is so highly conserved in BRCA2 that there might be other interactions affecting residue conservation, making it hard to know if the motif is a good description.

PALB2_WD40 (PF16756) Partner and localizer of BRCA2 WD40 domain (Stochiometry: 1 : 1)