Signaling by Unfolding

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Science  01 Feb 2013:
Vol. 339, Issue 6119, pp. 490
DOI: 10.1126/science.339.6119.490-b

In response to DNA damage, nuclear p53, a tumor suppressor, induces expression of the p53 up-regulated modulator of apoptosis (PUMA). PUMA in turn regulates the activity of cytosolic p53. In the cytosol, p53 is sequestered by the anti-apoptotic protein BCL-xL, a member of the BCL-2 family of anti-apoptotic proteins. PUMA disrupts this interaction and frees p53 to initiate apoptosis. BCL-2 proteins are composed of BCL-2 homology (BH) domains, and PUMA is a single–BH domain protein. Follis et al. used NMR spectroscopy and biophysical methods to show that PUMA is intrinsically unstructured, but that its BH3 domain folds upon binding to a hydrophobic groove in BCL-xL. NMR spectroscopy and x-ray crystallography showed that PUMA binding caused partial unfolding of two helices in BCL-xL. Although PUMA forms complexes with other anti-apoptotic complexes, it did not induce similar structural perturbations in these proteins. Structural data suggested that a π-stacking interaction between Trp-71 of PUMA and His-113 of BCL-xL was key to the destabilization of regions of the BCL-xL structure. Thus, the p53 apoptotic pathway is activated by regulated unfolding of an anti-apoptotic protein.

Nat. Chem. Biol. 10.1038/NCHEMBIO.1166 (2013).

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