title: Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Ranjani
authors.initials: R
authors.lastname: Varadan
authors.forename: Michael
authors.initials: M
authors.lastname: Assfalg
authors.forename: Shahri
authors.initials: S
authors.lastname: Raasi
authors.forename: Cecile
authors.initials: C
authors.lastname: Pickart
authors.forename: David
authors.initials: D
authors.lastname: Fushman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D008239:Lysine; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D025821:Polyubiquitin / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D014908:Triticum; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000737:chemistry*
chemical_list: D014452:Ubiquitins; C075986:diubiquitin conjugate; D025821:Polyubiquitin; D044764:Ubiquitin-Activating Enzymes; D008239:Lysine