Ionic polyphosphorylation of histidine repeat proteins by inorganic polyphosphate

Abstract

Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate that is present in nearly all organisms studied to date. A remarkable function of polyP involves its attachment to lysine residues via non-enzymatic post-translational modification (PTM) that is presumed to be covalent. Here, we show that proteins containing tracts of consecutive histidine residues exhibit a similar modification by polyP, which confers an electrophoretic mobility shift on NuPAGE gels. Our screen uncovered 30 human and yeast histidine repeat proteins that are specifically modified by polyP. This polyP modification is histidine-dependent and non-covalent in nature, though remarkably, it withstands harsh denaturing conditions--a hallmark of covalent PTMs. We have termed this interaction ionic histidine polyphosphorylation (iH-PPn) to describe its unique PTM-like properties. Importantly, we show that iH-PPn disrupts phase separation and phosphorylation activity of the human protein kinase DYRK1A, and inhibits the activity of the transcription factor MafB, highlighting iH-PPn as a potential hitherto unrecognized regulatory mechanism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/536149v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1ed34b7org.highwire.dtl.DTLVardef@200259org.highwire.dtl.DTLVardef@17a2954org.highwire.dtl.DTLVardef@12f5d04_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG