Mar 31, 2020

Ligand-induced conformational transitions in the activation mechanism of SHP2 tyrosine phosphatase

BioRxiv : the Preprint Server for Biology
Mario FruzangoharDavid L Adelson


SHP2 is a protein tyrosine phosphatase with a key role in multiple signaling pathways, including the RAS-MAPK cascade. Germline mutations in PTPN11, the gene encoding SHP2, occur in 50% of individuals affected by Noonan syndrome, whereas somatic mutations in this gene cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML), and are variably found in other pediatric hematologic malignancies and tumors. Inhibition of the wild-type protein has been recently demonstrated as a novel effective therapeutic strategy for many forms of cancer. Under basal conditions, wild-type SHP2 is inactive because its N-terminal Src homology 2 (N-SH2) domain blocks the active site of the protein tyrosine phosphatase (PTP) domain. Previous work established that binding of a phosphopeptide ligand to the N-SH2 domain causes SHP2 activation by favoring dissociation of the N-SH2 and PTP domains, however the conformational transitions of N-SH2 controlling ligand affinity and PTP dissociation are not well understood. Based on molecular simulations and free-energy calculations, we revealed a 20[A]-spanning allosteric network restraining the N-SH2 domain to two distinct states, a SHP2-activating and a stabilizing state. We find that ligand bin...Continue Reading

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Mentioned in this Paper

Pathogenic Aspects
Protein Function
Gene Expression
Comparative Genomic Analysis

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