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Key mechanism facilitating ubiquitin chain assembly resolved

June 2016. The protein ubiquitin regulates numerous essential processes in cells. Chains of ubiquitin molecules have different functions depending on the number of molecules involved as well as the type of linkage. Despite the important role of these polyubiquitin signals, the molecular basis on how the chains are generated remains elusive. In contrast to single attachments of ubiquitin to a substrate, building a ubiquitin chain challenges the cascade of different enzyemes involved with multiple conjugation events at the same molecule. This sequential assembly is a spatially dynamic process in which the distal tip of a growing chain constantly changes its position relativ to the active site of the enyzme complex. This causes chain assembly to slow down with increasing chain length.

Ubiquitin binding domains (UBDs) appear to be the key in facilitating chain assembly. New results from NMR-based analysis and in vitro ubiquitination reactions conducted by a team of scientists from Frankfurt, Berlin and Oxford provide a detailed molecular mechanism of how a ubiquitin binding domain stimulates ubiquitin polymerization. The study,  published recently in the journal Molecular Cell,  demonstrates that the CUE ubiquitin binding domain of Cue1 accelerates the elongation of ubiquitin chains by specific binding events that coordinate the spatial arrangement of the ubiquitin-conjugating enzyme Ubc7 with the distal end of nascent chains (image). Two parameters accelerated the assembly of ubiquitin chains: the increasing number of binding sites  for the CUE domain and the position of CUE binding within a growing chain. The new data show that disrupting this mechanism results in dysfunction of the endoplasmic reticulum-associated protein degradation pathway (ERAD) by a delayed turnover of substrates. More ...


Volker Dötsch
Buchmann Institute of Molecular Life Sciences
Institute of Biophysical Chemistry
Goethe University Frankfurt


Full Reference:
von Delbrück M, Kniss A, Rogov VV, Pluska L, Bagola K, Löhr F, Güntert P, Sommer T, Dötsch V (2016) The CUE domain of cue1 aligns growing ubiquitin chains with ubc7 for rapid elongation. Mol Cell 62, published online 2 June 2016 [Link]