Chain Assembly and Disassembly Processes Differently Affect the Conformational Space of Ubiquitin Chains

Kniss, Andreas; Schuetz, Denise; Kazemi, Sina; Pluska, Lukas; Spindler, Philipp E.; Rogov, Vladimir V.; Husnjak, Koraljka; Đikić, Ivan; Güntert, Peter; Sommer, Thomas; Prisner, Thomas F.; Dötsch, Volker

doi:10.1016/j.str.2017.12.011

Cited by 17 publications

(24 citation statements)

References 39 publications

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“…Interestingly, we also observed a pronounced CSP of K48 in ubiquitin indicating that this residue contributes to binding of the UBA domain. As shown for other systems, such an interaction can compete with the enzymatic activity of UBC domains (Kniss et al, 2018). By employing a model based on two different binding sites in diubiquitin (Raasi et al, 2005), we quantitatively analyzed the NMR titration experiments and calculated K D values (Fig 4E and F).…”

Section: Characterization Of Uba Domain Binding To Differently Linkedmentioning

confidence: 77%

“…Recently, low-affinity interactions with the acceptor ubiquitin (Ub A ) mediated by ubiquitin-binding domains (UBDs) or other ubiquitin-binding interfaces outside the catalytically active UBC domain of E2 enzymes have emerged as key regulatory factors for the efficient assembly of ubiquitin chains (Wright et al, 2016;Watson et al, 2019). For example, the Cue1 protein recruits the K48-specific E2 enzyme Ubc7 to the tip of a ubiquitin chain through association with the penultimate ubiquitin moiety and therefore facilitates the elongation of K48-linked polyubiquitin (von Delbr€ uck et al, 2016;Kniss et al, 2018). Similarly, the formation of K63-linked chains by Ubc13 relies on its cofactor Uev1a, which aligns the immediate Ub A molecule with the active site of Ubc13 (Pastushok et al, 2005;Branigan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63‐branched ubiquitin chains

et al. 2021

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The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Uniquely among E2 enzymes, Ubc1 and Ube2K harbor a ubiquitin-binding UBA domain with unknown function. We found that this UBA domain preferentially interacts with ubiquitin chains linked through lysine 63 (K63). Based on structural modeling, in vitro ubiquitination experiments, and NMR studies, we propose that the UBA domain aligns Ubc1 with K63linked polyubiquitin and facilitates the selective assembly of K48/ K63-branched ubiquitin conjugates. Genetic and proteomics experiments link the activity of the UBA domain, and hence the formation of this unusual ubiquitin chain topology, to the maintenance of cellular proteostasis.

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Section: Characterization Of Uba Domain Binding To Differently Linkedmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63‐branched ubiquitin chains

et al. 2021

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“…One reason for this specificity is that the linkage position determines the morphology of Ub chains, as was shown in various structural studies of differently linked Ub dimers and longer chains [6]. On the other hand, for a single linkage type, very different conformations can be found as well (PDB ID: 1F9J (open), 1TBE (compact), 1AAR (closed)) which indicates that a Ub chain can adopt different structures in solution [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Simulating and analysing configurational landscapes of protein–protein contact formation

Berg

Peter

2019

Interface Focus.

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Interacting proteins can form aggregates and protein–protein interfaces with multiple patterns and different stabilities. Using molecular simulation one would like to understand the formation of these aggregates and which of the observed states are relevant for protein function and recognition. To characterize the complex configurational ensemble of protein aggregates, one needs a quantitative measure for the similarity of structures. We present well-suited descriptors that capture the essential features of non-covalent protein contact formation and domain motion. This set of collective variables is used with a nonlinear multi-dimensional scaling-based dimensionality reduction technique to obtain a low-dimensional representation of the configurational landscape of two ubiquitin proteins from coarse-grained simulations. We show that this two-dimensional representation is a powerful basis to identify meaningful states in the ensemble of aggregated structures and to calculate distributions and free energy landscapes for different sets of simulations. By using a measure to quantitatively compare free energy landscapes we can show how the introduction of a covalent bond between two ubiquitin proteins at different positions alters the configurational states of these dimers.

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“…The hydrophobic patch, as an example, that was reported to serve as an interaction hot spot for K48-linked chains, is apparently not accessible in various structures that were determined for this linkage type [17]. Consequently, additional efforts are required to elucidate the entire conformational ensemble of Ub dimers and, thus, the Ub code [18].…”

Section: Introductionmentioning

confidence: 99%

Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers

et al. 2018

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Covalent modification of proteins by ubiquitin or ubiquitin chains is one of the most prevalent post-translational modifications in eukaryotes. Different types of ubiquitin chains are assumed to selectively signal respectively modified proteins for different fates. In support of this hypothesis, structural studies have shown that the eight possible ubiquitin dimers adopt different conformations. However, at least in some cases, these structures cannot sufficiently explain the molecular basis of the selective signaling mechanisms. This indicates that the available structures represent only a few distinct conformations within the entire conformational space adopted by a ubiquitin dimer. Here, molecular simulations on different levels of resolution can complement the structural information. We have combined exhaustive coarse grained and atomistic simulations of all eight possible ubiquitin dimers with a suitable dimensionality reduction technique and a new method to characterize protein-protein interfaces and the conformational landscape of protein conjugates. We found that ubiquitin dimers exhibit characteristic linkage type-dependent properties in solution, such as interface stability and the character of contacts between the subunits, which can be directly correlated with experimentally observed linkage-specific properties.

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Chain Assembly and Disassembly Processes Differently Affect the Conformational Space of Ubiquitin Chains

Cited by 17 publications

References 39 publications

The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63‐branched ubiquitin chains

The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63‐branched ubiquitin chains

Simulating and analysing configurational landscapes of protein–protein contact formation

Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers

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