期刊
ONCOGENE
卷 19, 期 10, 页码 1245-1256出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1203434
关键词
tumour suppressor; stability; denaturation; activity; protein
The tumour suppressor p53 is mutated in half of all human cancers, most frequently with missense substitutions in its core domain. We present a new assessment of the mutation database based on quantitative folding and DNA-binding studies of the isolated core domain. Our data identify five distinct mutant classes that correlate with four well-defined regions of the core domain structure. On extrapolation to 37 degrees C the wild-type protein has a stability of 3.0 kcal/mol, This also emerges as an oncogenic threshold: all beta-sandwich mutants destabilized by this amount (50% denatured) are expected to promote cancer. Other weakly destabilizing mutations are restricted to loop 3 in the DNA-binding region, Drugs that stabilize mutant p53 folding have the potential to reactivate apoptotic signalling pathways in tumour cells either by transactivation-dependent or independent pathways. Using an affinity ligand as a proof of principle we have recovered the thermodynamic stability of the hotspot G245S. With reference states for the five mutant classes as a guide, future therapeutic strategies may similarly stabilize partially structured or binding states of mutant p53 that restore limited p53 pathways to tumour suppression.
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