Structural analysis of genetic variants of the human tumor suppressor Palb2 coiled-coil domain

Homologous recombination (HR) is an obligate pathway to repair DNA lesions and maintain genome integrity. The tumor suppressor Palb2 is an integral part of the HR pathway that functionally connects BRCA proteins at the site of DNA damage. The N-terminal coiled-coil domain in Palb2 switches from an inactive to an active complex during HR. In the inactive form, Palb2 forms homodimers, and during HR, it assumes the active state, forming a heterodimeric complex with BRCA1. However, the structural details of the human Palb2 coiled-coil domain are unknown. About 600 missense variants have been reported in Palb2, and several are in the coiled-coil domain. The structure-function relationship of such variants is poorly understood, which challenges genetic counseling. Here, we report the solution structure of the human Palb2 coiled-coil domain, which forms an antiparallel homodimer. We then use the structure to study the effect of a few well-characterized missense mutations on the fold and interactions of the Palb2 coiled-coil domain. The structural impact of mutations correlates excellently with their efficiency in homologous recombination, signifying that the approach can be exploited to study other genetic variations in the Palb2.