Mixed-Linkage Ubiquitin Chains Send Mixed Messages

Mark A. Nakasone, Nurit Livnat-Levanon, Michael H. Glickman, Robert E. Cohen, David Fushman
2013 Structure  
Research on ubiquitin (Ub) signaling has focused primarily on homogeneously linked polyUb. Although polyUb containing different linkages within the same chain exist, their structures and signaling properties are unknown. These mixed-linkage chains could be unbranched (i.e., no more than one lysine or methionine linkage per Ub) or branched. Here, we examined the structure, dynamics, receptor selectivity, and disassembly of branched and unbranched tri-Ub containing both K48 and K63 linkages. Each
more » ... linkage was virtually indistinguishable from its counterpart in homogeneously linked polyUb. Linkageselective receptors from hHR23A and Rap80 preferentially bound to the K48 or K63 linkages in the branched trimer. Linkage-selective deubiquitinases specifically cleaved their cognate Ub-Ub linkages in mixed-linkage chains, and the 26S proteasome recognized and processed branched tri-Ub. We conclude that mixed-linkage chains retain the distinctive signaling properties of their K48 and K63 components and that these multiple signals can be recognized by multiple linkage-specific receptors. Finally, we propose a new, comprehensive notation for Ub and Ub-like polymers. Structure Mixed-Linkage Ubiquitin Chains Send Mixed Messages 728 Structure 21, 727-740, May 7,
doi:10.1016/j.str.2013.02.019 pmid:23562397 pmcid:PMC3654000 fatcat:tay2lgoyzrbvncm55lfhxi5hka