A single amino-acid substitution intheEtsdomainalters coreDNAbinding specificity ofEtsltothat oftherelated transcription factors Elfi andE74

Etsproteins formafamily ofsequence specific DNA binding proteins whichbindDNA through a 85 aminoacids conserved domain, theEtsdomain, whose sequence isunrelated toanyother characterized DNA binding domain. Unlike allother knownEtsproteins, whichbindspecific DNAsequences centered over either GGAAorGGATcoremotifs, E74andElf 1 selectively bind toGGAAcorecontaining sites. Elf 1and E74differ fromother Etsproteins inthree residues located inanotherwise highly conserved region ofthe Etsdomain, referred toasconserved region Ill (CRIII). Weshowthat arestricted selectivity forGGAAcorecontaining sites couldbeconferred toEtslupon changing asingle lysine residue within CRIII tothe threonine foundinElf 1 andE74atthisposition. Conversely, thereciprocal mutation inElf 1confers to this protein theability tobind toGGATcorecontaining EBS.This, together withthefact that mutation oftwo invariant arginine residues inCRIII abolishes DNA binding, Indicates thatCRIII plays akeyrole inEts domainrecognition oftheGGAA/Tcoremotif andlead ustodiscuss a modelofEtsproteins -coremotif interaction.