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Protein Sci. 2015 Feb;24(2):182-9. doi: 10.1002/pro.2603. Epub 2015 Jan 15.

Intrinsic site-selectivity of ubiquitin dimer formation.

Author information

1
Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin.

Abstract

The post-translational modification of proteins with ubiquitin can take on many forms, including the decoration of substrates with polymeric ubiquitin chains. These chains are linked through one of the seven lysine residues in ubiquitin, with the potential to form a panoply of linkage combinations as the chain length increases. The ensuing structural diversity of modifications serves a variety of signaling functions. Still, some linkages are present at a much higher level than others in cellulo. Although ubiquitination is an enzyme-catalyzed process, the large disparity of abundancies led us to the hypothesis that some linkages might be intrinsically faster to form than others, perhaps directing the course of enzyme evolution. Herein, we assess the kinetics of ubiquitin dimer formation in an enzyme-free system by measuring the rate constants for thiol-disulfide interchange between appropriate ubiquitin variants. Remarkably, we find that the kinetically expedient linkages correlate with those that are most abundant in cellulo. As the abundant linkages also appear to function more broadly in cellulo, this correlation suggests that the more accessible chains were selected for global roles.

KEYWORDS:

mixed disulfide; protein-protein interaction; thiol-disulfide interchange; ubiquitin

PMID:
25401704
PMCID:
PMC4315656
DOI:
10.1002/pro.2603
[Indexed for MEDLINE]
Free PMC Article

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