HIGHLIGHTS Outline of EGF dependent in-vivo phosphotyrosine signaling in lung tissue A peptide based screen identifies proteins recruited to regulated phosphotyrosine sites in lung tissue Several somatic mutations affect proline residues within position +3 of regulated phosphotyrosine sites and introduce molecular switches A lung cancer oncogenic mutation in EGFR causes aberrant activation of phosphorylation signaling pathways by switching of a recruited protein complex Cancer mutations in vicinity of phosphotyrosine sites induce molecular switches that alter protein signaling networks Introduction of cutting-edge LC-MS instrumentation and DIA enables scalable, rapid and highthroughput analysis of phosphotyrosine site interactions
Highlights d The conserved PP4 holoenzyme binds to FxxP motifs that provide specificity d FxxP motifs bind to a conserved binding pocket on PP4 regulatory subunit d Binding to FxxP motifs can be regulated through phosphorylation d PP4 binding to an FxxP motif in WAPL regulates its cohesin release activity
A manganese-dependent cysteinyl-glycine hydrolysing activity has been purified to electrophoretic homogeneity from bovine lens. The characterization of the purified enzyme (molecular mass of the native protein, molecular mass of the subunit and extensive primary structure analysis) allowed the unequivocal attribution of the cysteinyl-glycine hydrolysing activity, which is usually associated with alanyl aminopeptidase (EC 3.4.11.2) or membrane-bound dipeptidase (EC 3.4.13.19), to LAP (leucyl aminopeptidase; EC 3.4.11.1). Analysis of the pH dependence of Cys-Gly hydrolysis catalysed by LAP, supported by a molecular modelling approach to the enzyme-substrate conformation, gave insights into the ability of the enzyme to recognize Cys-Gly as a substrate. Due to the effectiveness of LAP in hydrolysing Cys-Gly (K(m)=0.57 mM, kcat=6.0x10(3) min(-1) at pH 7.4 and 25 degrees C) with respect to other dipeptide substrates, a new role for this enzyme in glutathione turnover is proposed.
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