Structural Determinants for Selective Recognition of a Lys48-Linked Polyubiquitin Chain by a UBA Domain

• DOI: 10.1016/j.molcel.2005.05.013
• Publication Date: 2005-06-10T15:55:01Z
• Authors: Ranjani Varadan; Michael Assfalg; Shahri Raasi; Cecile Pickart; David Fushman
• Keywords: Models, Molecular; 0301 basic medicine; Binding Sites; Magnetic Resonance Spectroscopy; Protein Conformation; Lysine; Cell Biology; Ubiquitin-Activating Enzymes; Protein Structure, Secondary; 03 medical and health sciences; Amino Acid Sequence; Polyubiquitin; nmr; ubiquitin; polyubiquitin; Molecular Biology; Ubiquitins; Triticum

Although functional diversity in polyubiquitin chain signaling has been ascribed to the ability of differently linked chains to bind in a distinctive manner to effector proteins, structural models of such interactions have been lacking. Here, we use NMR to unveil the structural basis of selective recognition of Lys48-linked di- and tetraubiquitin chains by the UBA2 domain of hHR23A. Although the interaction of UBA2 with Lys48-linked diubiquitin involves the same hydrophobic surface on each ubiquitin unit as that utilized in monoubiquitin:UBA complexes, our results show how the "closed" conformation of Lys48-linked diubiquitin is crucial for high-affinity binding. Moreover, recognition of Lys48-linked diubiquitin involves a unique epitope on UBA, which allows the formation of a sandwich-like diubiqutin:UBA complex. Studies of the UBA-tetraubiquitin interaction suggest that this mode of UBA binding to diubiquitin is relevant for longer chains.