Abstract
Ubiquitin (Ub) can generate versatile molecular signals and lead to different celluar fates. The functional poly-valence of Ub is believed to be resulted from its ability to form distinct polymerized chains with eight linkage types. To provide a full picture of ubiquitin code, we explore the binding landscape of two free Ub monomers and also the functional landscapes of of all eight linkage types by theoretical modeling. Remarkably, we found that most of the compact structures of covalently connected dimeric Ub chains (diUbs) pre-exist on the binding landscape. These compact functional states were subsequently validated by corresponding linkage models. This leads to the proposal that the folding architecture of Ub monomer has encoded all functional states into its binding landscape, which is further selected by different topologies of polymeric Ub chains. Moreover, our results revealed that covalent linkage leads to symmetry breaking of interfacial interactions. We further propose that topological constraint not only limits the conformational space for effective switching between functional states, but also selects the local interactions for realizing the corresponding biological function. Therefore, the topological constraint provides a way for breaking the binding symmetry and reaching the functional specificity. The simulation results also provide several predictions that qualitatively and quantitatively consistent with experiments. Importantly, the K48 linkage model successfully predicted intermediate states. The resulting multi-state energy landscape was further employed to reconcile the seemingly contradictory experimental data on the conformational equilibrium of K48-diUb. Our results further suggest that hydrophobic interactions are dominant in the functional landscapes of K6-, K11-, K33- and K48 diUbs, while electrostatic interactions play a more important role in the functional landscapes of K27, K29, K63 and linear linkages.
Highlights
Ubiquitin (Ub) was discovered in the mid-1970s [1] and has been found to ubiquitously exist in eukaryotes
The electrostatic interactions in our model were calculated by the Debye-Huckel model whose parameters have been carefully tested in our previous works [24,28]
To further model the hydrophobic interactions, we introduced EHP to account for the strength of hydrophobic forces which was calibrated according to available experimental data, especially the apparent binding affinity between Ub units which has been measured to be about 5mM [22]
Summary
Ubiquitin (Ub) was discovered in the mid-1970s [1] and has been found to ubiquitously exist in eukaryotes. Extensive studies suggested that the former usually takes action in proteasomal degradation (the most common fate of a ubiquitinated protein), while the latter plays non-degradative roles in cell signalling, such as endocytosis and DNA damage repair [8,9,10]. A few recent work reported that K11 linkage chain has non-degradative roles and acts as potent proteasomal degradation signals in diverse cellular pathways [11,12,13]. This is a surprise finding because K48-linked chains have always been considered to be the unique destruction tag for unneeded proteins in cells. Very little is known about the remaining five atypical linkage types [4,14,15]
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