Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA

Publisher Website
Google Scholar
Abstract
Atherosclerotic plaques form when blood flow is disturbed and unusual patterns of mechanical stress are applied to the blood vessel wall. The endothelial cells lining these vessels play an important role in the development of the disease. A study using cultured aortic endothelial cells now shows that three proteins expressed in endothelial cells form a mechanosensory complex, and each one has distinct functions in transducing mechanical force into a biochemical signal inside the cell. This can explain how blood flow stimulates endothelial cell responses and how atherosclerotic plaques might be initiated. The human Rad50/Mre11/Nbs1 complex (hR/M/N) functions as an essential guardian of genome integrity by directing the proper processing of DNA ends, including DNA breaks1. This biological function results from its ability to tether broken DNA molecules2,3. hR/M/N's dynamic molecular architecture consists of a globular DNA-binding domain from which two 50-nm-long coiled coils protrude. The coiled coils are flexible4 and their apices can self-associate5. The flexibility of the coiled coils allows their apices to adopt an orientation favourable for interaction. However, this also allows interaction between the tips of two coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Here we show that the dynamic architecture of hR/M/N is markedly affected by DNA binding. DNA binding by the hR/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favours intercomplex associations needed for DNA tethering. The hR/M/N complex thus is an example of a biological nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nm distant.