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

Mohanty, Priyesh; Agrata, Rashmi; Habibullah, Batul Ismail; Arun, G S; Das, Ranabir

doi:10.7554/elife.49223

Cited by 16 publications

(15 citation statements)

References 72 publications

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“…Conversion of glutamine into glutamate by OspI leads to the inhibition of the synthesis of polyubiquitin chain and UBC13/TRAF6, which resulted in inhibiting the activation of NF-κB. Interestingly, deamidation occurs outside the UBC13/TRAF6 interaction, but changing the salt-bridge interaction inhibits regular interaction between UBC13 and TRAF6 [ 188 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

et al. 2022

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Different gastrointestinal pathogens cause diarrhea which is a very common problem in children aged under 5 years. Among bacterial pathogens, Shigella is one of the main causes of diarrhea among children, and it accounts for approximately 11% of all deaths among children aged under 5 years. The case-fatality rates for Shigella among the infants and children aged 1 to 4 years are 13.9% and 9.4%, respectively. Shigella uses unique effector proteins to modulate intracellular pathways. Shigella cannot invade epithelial cells on the apical site; therefore, it needs to pass epithelium through other cells rather than the epithelial cell. After passing epithelium, macrophage swallows Shigella, and the latter should prepare itself to exhibit at least two types of responses: (I) escaping phagocyte and (II) mediating invasion of and injury to the recurrent PMN. The presence of PMN and invitation to a greater degree resulted in gut membrane injuries and greater bacterial penetration. Infiltration of Shigella to the basolateral space mediates (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In this review, an attempt is made to explain the role of each factor in Shigella infection.

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Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

et al. 2022

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“…Our results also uncover the underlying mechanism by which bacterial deamidation of NEDD8 inactivates CRLs. We have previously shown that the deamidation of the E2 enzyme-UBC13 by the Shigella flexneri deamidase -OspI triggers an intramolecular salt-bridge formation, inhibiting its association with the cognate RING E3 ligase -TRAF6 (37). We show here by MD simulations that deamidation at Q40 triggers the formation of an intramolecular salt bridge between E40 and R74.…”

Section: Discussionmentioning

confidence: 63%

NEDD8 Deamidation Inhibits Cullin RING Ligase Dynamics

2021

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Cullin-RING ligases (CRLs) are a significant subset of Ubiquitin E3 ligases that regulate multiple cellular substrates involved in innate immunity, cytoskeleton modeling, and cell cycle. The glutamine deamidase Cycle inhibitory factor (Cif) from enteric bacteria inactivates CRLs to modulate these processes in the host cell. The covalent attachment of a Ubiquitin-like protein NEDD8 catalytically activates CRLs by driving conformational changes in the Cullin C-terminal domain (CTD). NEDDylation results in a shift from a compact to an open CTD conformation through non-covalent interactions between NEDD8 and the WHB subdomain of CTD, eliminating the latter’s inhibitory interactions with the RING E3 ligase-Rbx1/2. It is unknown whether the non-covalent interactions are sufficient to stabilize Cullin CTD’s catalytic conformation. We studied the dynamics of Cullin-CTD in the presence and absence of NEDD8 using atomistic molecular dynamics (MD) simulations. We uncovered that NEDD8 engages in non-covalent interactions with 4HB/αβ subdomains in Cullin-CTD to promote open conformations. Cif deamidates glutamine 40 in NEDD8 to inhibit the conformational change in CRLs by an unknown mechanism. We investigated the effect of glutamine deamidation on NEDD8 and its interaction with the WHB subdomain post-NEDDylation using MD simulations and NMR spectroscopy. Our results suggest that deamidation creates a new intramolecular salt bridge in NEDD8 to destabilize the NEDD8/WHB complex and reduce CRL activity.

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“…Surface electrostatic potential analysis of hnRNPA1 RRMs indicates the presence of distinct, oppositely charged surfaces, which suggests the possibility of encounter complex formation through these complementary surfaces . The role of long-range electrostatic interactions in driving the formation of nonspecific encounter complexes − during protein–protein association is well-established for folded proteins. Moreover, repulsive interactions between like-charged surfaces of RRMs could prevent the establishment of long-range structural order within condensates and promote “liquid-like” dynamics.…”

Section: Charge-rich Domains Can Influence Phase Behavior Through Non...mentioning

confidence: 99%

Principles Governing the Phase Separation of Multidomain Proteins

et al. 2022

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A variety of membraneless organelles, often termed “biological condensates”, play an important role in the regulation of cellular processes such as gene transcription, translation, and protein quality control. On the basis of experimental and theoretical investigations, liquid–liquid phase separation (LLPS) has been proposed as a possible mechanism for the origin of biological condensates. LLPS requires multivalent macromolecules that template the formation of long-range, intermolecular interaction networks and results in the formation of condensates with defined composition and material properties. Multivalent interactions driving LLPS exhibit a wide range of modes from highly stereospecific to nonspecific and involve both folded and disordered regions. Multidomain proteins serve as suitable macromolecules for promoting phase separation and achieving disparate functions due to their potential for multivalent interactions and regulation. Here, we aim to highlight the influence of the domain architecture and interdomain interactions on the phase separation of multidomain protein condensates. First, the general principles underlying these interactions are illustrated on the basis of examples of multidomain proteins that are predominantly associated with nucleic acid binding and protein quality control and contain both folded and disordered regions. Next, the examples showcase how LLPS properties of folded and disordered regions can be leveraged to engineer multidomain constructs that form condensates with the desired assembly and functional properties. Finally, we highlight the need for improvements in coarse-grained computational models that can provide molecular-level insights into multidomain protein condensates in conjunction with experimental efforts.

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

Cited by 16 publications

References 72 publications

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

NEDD8 Deamidation Inhibits Cullin RING Ligase Dynamics

Principles Governing the Phase Separation of Multidomain Proteins

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