biostudies-literatureUnknownJiang ZNIGMS NIH HHSMulti-domain signaling enzymes are often regulated through extensive inter-domain interactions, and disruption of inter-domain interfaces by mutations can lead to aberrant signaling and diseases. For example, the tyrosine phosphatase SHP2 contains two phosphotyrosine recognition domains that auto-inhibit its catalytic domain. SHP2 is canonically activated by binding of these non-catalytic domains to phosphoproteins, which destabilizes the auto-inhibited state, but numerous mutations at the main auto-inhibitory interface have been shown to hyperactivate SHP2 in cancers and developmental disorders. Hundreds of clinically observed mutations in SHP2 have not been characterized, but their locations suggest alternative modes of dysregulation. We performed deep mutational scanning on full-length bioRxiv : the preprint server for biology2024.05.13.593907https://www.ebi.ac.uk/biostudies/studies/S-EPMC11291063biostudies-literatureDeep mutational scanning of a multi-domain signaling protein reveals mechanisms of regulation and pathogenicity.PMC11291063R35 GM138014van Vlimmeren AEJiang ZSemmelman AKarandur DShah NHfalseDeep mutational scanning of a multi-domain signaling protein reveals mechanisms of regulation and pathogenicity.Multi-domain signaling enzymes are often regulated through extensive inter-domain interactions, and disruption of inter-domain interfaces by mutations can lead to aberrant signaling and diseases. For example, the tyrosine phosphatase SHP2 contains two phosphotyrosine recognition domains that auto-inhibit its catalytic domain. SHP2 is canonically activated by binding of these non-catalytic domains to phosphoproteins, which destabilizes the auto-inhibited state, but numerous mutations at the main auto-inhibitory interface have been shown to hyperactivate SHP2 in cancers and developmental disorders. Hundreds of clinically observed mutations in SHP2 have not been characterized, but their locations suggest alternative modes of dysregulation. We performed deep mutational scanning on full-length 2024-01-01T00:00:00Z2024 Nov2026-07-01T03:18:02.339Z2024-11-08T11:08:34.398ZS-EPMC112910633909179810.1101/2024.05.13.593907