Cross β amyloid assemblies as complex catalytic machinery

Pal, Sumit; Goswami, Surashree; Das, Dibyendu

doi:10.1039/d1cc02880d

Cited by 17 publications

(18 citation statements)

References 96 publications

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“…As such, anchoring of the β-lactam substrate occurs on the fibrils surface primarily via the lysines' amine sidechains (marked in blue). Similar behavior of de-novo amphiphilic β-sheet amyloidogenic structure decorated with lysines was previously shown to exhibit catalytic activity towards enantioselective chemical reactions 33,34 .…”

Section: Discussionsupporting

confidence: 65%

Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics

Arad

Golan

Rapaport

et al. 2023

Preprint

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Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze breakup of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-bond four-member ring of nitrocefin, a widely used β-lactam surrogate. Microscopic and spectroscopic analyses of several PSMα3 variants and correlation with their catalytic activities allowed mapping of the catalytic sites on the amyloid fibrils surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine residue array. This study unveils a previously unknown role of functional bacterial amyloids as catalytic agents for antibiotic compounds, pointing to possible mechanisms for antibiotic resistance of bacteria.

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Section: Discussionsupporting

confidence: 65%

Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics

Arad

Golan

Rapaport

et al. 2023

Preprint

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“…Nonetheless, empirical determination for the dynamic protein-protein binding and dissociation in cell levels is needed, so as to build the big picture. For example, formation of an intracellular large protein complex may involve changes in protein conformations, enzymatic cleaves, energy requirement, heat release, and interactions with small molecules, ions, and/or amino acids [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

Section: Protein Interaction Network In Normal Signaling and Diseasesmentioning

confidence: 99%

WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners

Liu

Nagarajan

Chiang

et al. 2022

Cells

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Tumor suppressor WWOX inhibits cancer growth and retards Alzheimer’s disease (AD) progression. Supporting evidence shows that the more strongly WWOX binds intracellular protein partners, the weaker is cancer cell growth in vivo. Whether this correlates with retardation of AD progression is unknown. Two functional forms of WWOX exhibit opposite functions. pY33-WWOX is proapoptotic and anticancer, and is essential for maintaining normal physiology. In contrast, pS14-WWOX is accumulated in the lesions of cancers and AD brains, and suppression of WWOX phosphorylation at S14 by a short peptide Zfra abolishes cancer growth and retardation of AD progression. In parallel, synthetic Zfra4-10 or WWOX7-21 peptide strengthens the binding of endogenous WWOX with intracellular protein partners leading to cancer suppression. Indeed, Zfra4-10 is potent in restoring memory loss in triple transgenic mice for AD (3xTg) by blocking the aggregation of amyloid beta 42 (Aβ42), enhancing degradation of aggregated proteins, and inhibiting activation of inflammatory NF-κB. In light of the findings, Zfra4-10-mediated suppression of cancer and AD is due, in part, to an enhanced binding of endogenous WWOX and its binding partners. In this perspective review article, we detail the molecular action of WWOX in the HYAL-2/WWOX/SMAD4 signaling for biological effects, and discuss WWOX phosphorylation forms in interacting with binding partners, leading to suppression of cancer growth and retardation of AD progression.

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“…Short amyloid peptides capable of accessing paracrystalline phases have often been argued as the earliest protein folds. , As a systems chemistry approach, it would be intriguing to probe whether small molecular organic esters acting like coenzymes can interact with short peptides to drive the nonequilibrium polymerization and access catalytic self-assembled microphases as a function of time. , Herein, we show that a short peptide exploits a dynamic covalent linkage to interact with a negatively charged low molecular weight ester (coenzyme) leading to the formation of nonequilibrium amyloid polymers (Figure ). The polymers demonstrate covalent catalysis to subsequently degrade the coenzyme providing negative feedback toward their assembly process resulting in depolymerization.…”

mentioning

confidence: 95%

Nonequilibrium Amyloid Polymers Exploit Dynamic Covalent Linkage to Temporally Control Charge-Selective Catalysis

et al. 2022

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Extant proteins exploit thermodynamically activated negatively charged coenzymes and hydrotropes to temporally access mechanistically important conformations that regulate vital biological functions, from metabolic reactions to expression modulation. Herein, we show that a short amyloid peptide can bind to a small molecular coenzyme by exploiting reversible covalent linkage to polymerize and access catalytically proficient nonequilibrium amyloid microphases. Subsequent hydrolysis of the activated coenzyme leads to depolymerization, realizing a variance of the surface charge of the assembly as a function of time. Such temporal change of surface charge dynamically modulates catalytic activities of the transient assemblies as observed in highly evolved modern-day biocatalysts.

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Cross β amyloid assemblies as complex catalytic machinery

Abstract: How modern enzymes evolved as complex catalytic machineries to facilitate diverse chemical transformations is an open question for the emerging field of systems chemistry. Inspired by Nature’s ingenuity in creating...

Cited by 17 publications

References 96 publications

Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics

Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics

WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners

Nonequilibrium Amyloid Polymers Exploit Dynamic Covalent Linkage to Temporally Control Charge-Selective Catalysis

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