Antagonism between binding site affinity andconformational dynamics tunes alternativecis-interactions within Shp2

摘要

Protein functions are largely affected by their conformations. This is exemplified in proteinscontaining modular domains. However, the evolutionary dynamics that define and adapt theconformation of such modular proteins remain elusive. Here we show that cis-interactionsbetween the C-terminal phosphotyrosines and SH2 domain within the protein tyrosinephosphatase Shp2 can be tuned by an adaptor protein, Grb2. The competitiveness of twophosphotyrosines, namely pY542 and pY580, for cis-interaction with the same SH2 domain isgoverned by an antagonistic combination of contextual amino acid sequence and position ofthe phosphotyrosines. Specifically, pY580 with the combination of a favourable position andan adverse sequence has an overall advantage over pY542. Swapping the sequences ofpY542 and pY580 results in one dominant form of cis-interaction and subsequently inhibitsthe trans-regulation by Grb2. Thus, the antagonistic combination of sequence and positionmay serve as a basic design principle for proteins with tunable conformations.