Cracking the 'ubiquitin code': The evolving picture of the structure and molecular recognition of polyubiquitin signals.




Dr. David Fushman


Department of Chemistry and Biochemistry, University of Maryland






Ubiquitination is a critical protein post-translational modification of proteins involved in a variety of vital processes in eukaryotic cells. The ability of a small protein ubiquitin to act as a versatile molecular signal is due to its ability to form polymeric chains in which ubiquitin monomers are linked through various lysines. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is believed to be determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest that they play important regulatory roles in growth, development, and immune system pathways, however, the physical/structural basis of their interactions with receptors is poorly understood. By combining solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we characterized the structure and dynamics of all lysine-linked di-ubiquitins. We found that polyubiquitins are conformationally heterogeneous and in solution exist in dynamic equilibrium among many conformers. Interestingly, while each chain type exhibits unique conformational ensembles, there is surprising similarity of some conformers among chains of different linkages, suggesting common binding properties and potential overlap of biological function among different lysine linkages. Our binding studies confirmed this prediction. Implications of our findings to receptor recognition of various polyubiquitin signals will be discussed.


Suggested Readings

Stucture of a Diubiquitin.pdf Structural Determinants for Selective Recognition of a Lys48-Linked Polyubiquitin Chain by a UBA Domain
structure.pdf Linkage via K27 Bestows Ubiquitin Chains with Unique Properties among Polyubiquitins
The Scientist On the Chain Gang.pdf More than simply helping haul out a cell’s garbage, ubiquitin, with its panoply of chain lengths and shapes, marks and regulates many unrelated cellular processes.

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