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

• Published in: Molecular cell Vol. 18; no. 6; pp. 687 - 698
• Main Authors: Varadan, Ranjani, Assfalg, Michael, Raasi, Shahri, Pickart, Cecile, Fushman, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2005
• Subjects: Amino Acid Sequence; Binding Sites; Lysine; Magnetic Resonance Spectroscopy; Models, Molecular; Polyubiquitin - chemistry; Protein Conformation; Protein Structure, Secondary; Triticum; Ubiquitin-Activating Enzymes - metabolism; Ubiquitins - chemistry
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2005.05.013

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.