C-terminal acidic domain of ubiquitin-conjugating enzymes: A multi-functional conserved intrinsically disordered domain in family 3 of E2 enzymes

Arrigoni, Alberto; Grillo, Barbara; Vitriolo, Alessandro; Gioia, Luca De; Papaleo, Elena

doi:10.1016/j.jsb.2012.04.003

Cited by 17 publications

(22 citation statements)

References 111 publications

(177 reference statements)

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“…Although MD force fields have been developed to simulate protein folding, they have also proven useful to characterize the conformational ensembles of IDPs and unfolded proteins (Espinoza-Fonseca, 2009a; Cino et al, 2011; Arrigoni et al, 2012; Ganguly et al, 2012; Lindorff-Larsen et al, 2012; Knott and Best, 2012), especially when computational results are complemented by biophysical data. These studies contribute to enforce the applicability of classical MD to complex molecular ensembles.…”

Section: Discussionmentioning

confidence: 99%

“…By altering short- and long-range electrostatic interactions, phosphorylation could effectively modulate the conformational properties of this IDP, even far from the site of the modification (Johnson and Lewis, 2001; Arrigoni et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

“…The non-bonded pair list was updated every 10 steps and conformations were stored every 2 ps. The simulations were carried out in the presence of Na + and Cl − counterions, to simulate a physiological ionic strength (150 mM), according to a protocol previously employed for other IDPs (Espinoza-Fonseca, 2009a; Arrigoni et al, 2012). The length of each simulation (replicate, r.) ranged from 50 (r.1–r.6 and r.9) to 100 ns (r.7 and r.8).…”

Section: Methodsmentioning

confidence: 99%

“…Salt-bridge, aromatic, and hydrophobic interactions were analyzed as previously described (Tiberti and Papaleo, 2011; Arrigoni et al, 2012). In particular, a persistence cutoff of 20% and a distance cutoff of 0.5 nm were employed.…”

Section: Methodsmentioning

confidence: 99%

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Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation

et al. 2012

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Cyclin-dependent kinase inhibitors (CKIs) are key regulatory proteins of the eukaryotic cell cycle, which modulate cyclin-dependent kinase (Cdk) activity. CKIs perform their inhibitory effect by the formation of ternary complexes with a target kinase and its cognate cyclin. These regulators generally belong to the class of intrinsically disordered proteins (IDPs), which lack a well-defined and organized three-dimensional (3D) structure in their free state, undergoing folding upon binding to specific partners. Unbound IDPs are not merely random-coil structures, but can present intrinsically folded structural units (IFSUs) and collapsed conformations. These structural features can be relevant to protein function in vivo. The yeast CKI Sic1 is a 284-amino acid IDP that binds to Cdk1 in complex with the Clb5,6 cyclins, preventing phosphorylation of G1 substrates and, therefore, entrance to the S phase. Sic1 degradation, triggered by multiple phosphorylation events, promotes cell-cycle progression. Previous experimental studies pointed out a propensity of Sic1 and its isolated domains to populate both extended and compact conformations. The present contribution provides models for compact conformations of the Sic1 kinase-inhibitory domain (KID) by all-atom molecular dynamics (MD) simulations in explicit solvent and in the absence of interactors. The results are integrated by spectroscopic and spectrometric data. Helical IFSUs are identified, along with networks of intramolecular interactions. The results identify a group of putative hub residues and networks of electrostatic interactions, which are likely to be involved in the stabilization of the globular states.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation

et al. 2012

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“…So far, more than 30 E2s have been identified: most of them contain a highly conserved ubiquitin conjugation (UBC) domain [4], [6] that forms a covalent intermediate with ubiquitin via its catalytic Cys residue. Most diverse is the family of E3 proteins, which bring together ubiquitin-charged E2 (E2∼Ub) and the substrate protein; they bind to their substrate either directly or through adaptor/substrate recognition proteins [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

et al. 2013

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The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred – E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions.

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Using Biomolecular Simulations to Target Cdc34 in Cancer

Marco

Lambrughi

Papaleo

2018

Biomolecular Simulations in Structure‐Based Drug Discovery

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C-terminal acidic domain of ubiquitin-conjugating enzymes: A multi-functional conserved intrinsically disordered domain in family 3 of E2 enzymes

Cited by 17 publications

References 111 publications

Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation

Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

Using Biomolecular Simulations to Target Cdc34 in Cancer

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