Barnase–Barstar: From first encounter to final complex

Hoefling, Martin; Gottschalk, Kay E.

doi:10.1016/j.jsb.2010.03.001

Cited by 26 publications

(40 citation statements)

References 64 publications

(94 reference statements)

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“…As a control of the protocol, US simulations were performed to study the association between Barnase and Barstar (Figure S6, Table 1 and Table S1). The observed PMF profile and ΔG PMF (−12.6 kcal mol −1 ) of the Barnase/Barstar complex are consistent with the high-affinity of the complex (K d ~136 fM) and previous MD studies (Hoefling & Gottschalk 2010; Wang et al 2010).…”

Section: Resultssupporting

confidence: 90%

Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases

Mohanty

Rashmi

Habibullah

et al. 2019

Preprint

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26The deamidase OspI from enteric bacteria Shigella flexneri deamidates a glutamine residue in the 27 host ubiquitin-conjugating enzyme UBC13 and converts it to glutamate (Q100E). Consequently, its 28 polyubiquitination activity in complex with the RING-finger ubiquitin ligase TRAF6 and the downstream 29 NF-B inflammatory response is inactivated. The precise role of deamidation in inactivating the 30 UBC13/TRAF6 complex is unknown. We report that deamidation inhibits the interaction between 31 UBC13 and TRAF6 RING-domain (TRAF6 RING ) by perturbing both the native and transient 32 interactions. Deamidation creates a new intramolecular salt-bridge in UBC13 that competes with a 33 critical intermolecular salt-bridge at the native UBC13/TRAF6 RING interface. Moreover, the salt-bridge 34 competition prevents transient interactions necessary to form a typical UBC13/RING complex. 35Repulsion between E100 and the negatively charged surface of RING also prevents transient 36 interactions in the UBC13/RING complex. Our findings highlight a mechanism where a post-37 translational modification perturbs the conformation and stability of transient complexes to inhibit 38 protein-protein association. 39 40 41 42 43 44 45finger E3s like TRAF6 to synthesize K63-linked poly-Ub chains that function to activate DNA repair or 72 immune response (Matsuzawa et al. 2007). Apart from the E3s, UBC13 also binds a co-factor MMS2, 73 which does not activate UBC13 but maintains the linkage specificity of the poly-Ub chains synthesized 74 by UBC13 (Branigan et al. 2015). 75In this study, we have investigated the mechanisms underlying the inactivation of UBC13 76 upon deamidation using NMR spectroscopy, molecular dynamics (MD) simulations, and in-vitro 77 ubiquitination assays. We report that deamidation weakens the non-covalent interaction of UBC13 78 with RING-finger domain of TRAF6 (TRAF6 RING ), without perturbing UBC13 structure or the enzymatic 79 activity of UBC13. However, the underlying cause of reduced interaction is nonintuitive since Q100 is 80 in the vicinity of UBC13/TRAF6 RING interface but does not form any contact with the TRAF6 RING . 81Further studies showed that deamidation disrupts the interaction between UBC13 and TRAF6 RING by 82 three mechanisms: i) A new intramolecular R14/E100 salt-bridge appears in dUBC13, which competes 83 with a critical intermolecular salt-bridge in the native complex, ii) the salt-bridge competition also 84 perturbs the UBC13/TRAF6 RING transient complexes to inhibit association, and iii) repulsion between 85 the negatively charged E100 and the negatively charged interface of TRAF6 RING perturbs the transient 86 complexes to reduce association between UBC13 and TRAF6 RING . The effect of each mechanism on 87 the binding was confirmed by binding studies using appropriate substitutions in either UBC13 or 88 TRAF6 RING . The impact of deamidation on transient interactions was also observed using another 89 RING domain from RNF38, indicating that the mechanism could be ubiquitous for UBC13/RING 90 c...

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Section: Resultssupporting

confidence: 90%

Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases

Mohanty

Rashmi

Habibullah

et al. 2019

Preprint

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“…Furthermore, their simulations reveal that this protein-protein recognition process is mainly driven by the van der Waals and electrostatic interactions between two partner proteins. These results agree with the previous all-atom simulations 92 .…”

Section: Cg Models Of Proteinsupporting

confidence: 94%

Recent Advances in Transferable Coarse-Grained Modeling of Proteins

Kar

Feig

2014

Advances in Protein Chemistry and Structural Biology

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Computer simulations are indispensable tools for studying the structure and dynamics of biological macromolecules. Biochemical processes occur on different scales of length and time. Atomistic simulations cannot cover the relevant spatiotemporal scales at which the cellular processes occur. To address this challenge, coarse-grained (CG) modeling of the biological systems are employed. Over the last few years, many CG models for proteins continue to be developed. However, many of them are not transferable with respect to different systems and different environments. In this review, we discuss those CG protein models that are transferable and that retain chemical specificity. We restrict ourselves to CG models of soluble proteins only. We also briefly review recent progress made in the multi-scale hybrid all-atom/coarse-grained simulations of proteins.

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“…55,69,70 The complex has been used here as a guide for model refinement. The other complexes considered are: trypsin bound to a protein inhibitor (2ptc) and histidine-containing phosphocarrier protein HPr (1poh).…”

Section: Resultsmentioning

confidence: 99%

Specific and Non-Specific Protein Association in Solution: Computation of Solvent Effects and Prediction of First-Encounter Modes for Efficient Configurational Bias Monte Carlo Simulations

2013

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Weak and ultra-weak protein-protein association play a role in molecular recognition, and can drive spontaneous self-assembly and aggregation. Such interactions are difficult to detect experimentally, and are a challenge to the force field and sampling technique. A method is proposed to identify low-population protein-protein binding modes in aqueous solution. The method is designed to identify preferential first-encounter complexes from which the final complex(es) at equilibrium evolves. A continuum model is used to represent the effects of the solvent, which accounts for short- and long-range effects of water exclusion and for liquid-structure forces at protein/liquid interfaces. These effects control the behavior of proteins in close proximity and are optimized based on binding enthalpy data and simulations. An algorithm is described to construct a biasing function for self-adaptive configurational-bias Monte Carlo of a set of interacting proteins. The function allows mixing large and local changes in the spatial distribution of proteins, thereby enhancing sampling of relevant microstates. The method is applied to three binary systems. Generalization to multiprotein complexes is discussed.

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Barnase–Barstar: From first encounter to final complex

Cited by 26 publications

References 64 publications

Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases

Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases

Recent Advances in Transferable Coarse-Grained Modeling of Proteins

Specific and Non-Specific Protein Association in Solution: Computation of Solvent Effects and Prediction of First-Encounter Modes for Efficient Configurational Bias Monte Carlo Simulations

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