Molecular insights into polyubiquitin chain assembly: Crystal structure ofthe Mms2/Ubc13 heterodimer

While the signaling properties of ubiquitin depend on the topology of polyu biquitin chains, little is known concerning the molecular basis of specific ity in chain assembly and recognition. UEV/Ubc complexes have been implicat ed in the assembly of Lys63-linked polyubiquitin chains that act as a novel signal in postreplicative DNA repair and I kappaB alpha kinase activation. The crystal structure of the Mms2/Ubc13 heterodimer shows the active site of Ubc13 at the intersection of two channels that are potential binding sit es for the two substrate ubiquitins. Mutations that destabilize the heterod imer interface confer a marked UV sensitivity, providing direct evidence th at the intact heterodimer is necessary for DNA repair. Selective mutations in the channels suggest a molecular model for specificity in the assembly o f Lys63-linked polyubiquitin signals.