How it feels in a cell

Bonucci, Martina; Shu, Tong; Holt, Liam J.

doi:10.1016/j.tcb.2023.05.002

Cited by 17 publications

(7 citation statements)

References 124 publications

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“…We hypothesized that an IDR-based cellular volume sensor would alter its ensemble when the cell experiences volume-induced changes. One mechanism often invoked to explain this is that a decrease in cell volume would increase macromolecular crowding in the cytoplasm, which in turn would drive IDR compaction 41 . Cell volume increase should have the opposite effect ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Sequence-ensemble-function relationships for disordered proteins in live cells

Emenecker,

Guadalupe,

Shamoon

et al. 2023

Preprint

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Intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and play a variety of essential cellular roles. IDRs exist in a collection of structurally distinct conformers known as an ensemble. An IDR’s amino acid sequence determines its ensemble, which in turn can play an important role in dictating molecular function. Yet a clear link connecting IDR sequence, its ensemble properties, and its molecular function in living cells has not been directly established. Here, we set out to test this sequence-ensemble-function paradigm using a novel computational method (GOOSE) that enables the rational design of libraries of IDRs by systematically varying specific sequence properties. Using ensemble FRET, we measured the ensemble dimensions of a library of rationally designed IDRs in human-derived cell lines, revealing how IDR sequence influences ensemble dimensionsin situ.Furthermore, we show that the interplay between sequence and ensemble can tune an IDR’s ability to sense changes in cell volume - ade novomolecular function for these synthetic sequences. Our results establish biophysical rules for intracellular sequence-ensemble relationships, enable a new route for understanding how IDR sequences map to function in live cells, and set the ground for the design of synthetic IDRs withde novofunction.

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Section: Resultsmentioning

confidence: 99%

Sequence-ensemble-function relationships for disordered proteins in live cells

Emenecker,

Guadalupe,

Shamoon

et al. 2023

Preprint

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“…Although the intact cell represents an attractive system for studying the structural and functional organization of subcellular machines, interpreting the results obtained from such studies must consider that these interacting systems function inside the cell in a heterogeneous and highly volume-occupied or crowded environment. − These microenvironments may influence the reactivity and location of proteins and other biological macromolecules involved in essential processes, thus acting as nonspecific modulating factors of bacterial cellular functions. The purpose of this review is to emphasize that the mode of operation of critical bacterial cell cycle events depends not only on the specific molecular interactions between their components but also on nonspecific interactions with elements of their intracellular microenvironments.…”

Section: Introductionmentioning

confidence: 99%

Macromolecular Crowding, Phase Separation, and Homeostasis in the Orchestration of Bacterial Cellular Functions

Monterroso,

Margolin,

Boersma

et al. 2024

Chem. Rev.

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Macromolecular crowding affects the activity of proteins and functional macromolecular complexes in all cells, including bacteria. Crowding, together with physicochemical parameters such as pH, ionic strength, and the energy status, influences the structure of the cytoplasm and thereby indirectly macromolecular function. Notably, crowding also promotes the formation of biomolecular condensates by phase separation, initially identified in eukaryotic cells but more recently discovered to play key functions in bacteria. Bacterial cells require a variety of mechanisms to maintain physicochemical homeostasis, in particular in environments with fluctuating conditions, and the formation of biomolecular condensates is emerging as one such mechanism. In this work, we connect physicochemical homeostasis and macromolecular crowding with the formation and function of biomolecular condensates in the bacterial cell and compare the supramolecular structures found in bacteria with those of eukaryotic cells. We focus on the effects of crowding and phase separation on the control of bacterial chromosome replication, segregation, and cell division, and we discuss the contribution of biomolecular condensates to bacterial cell fitness and adaptation to environmental stress. CONTENTS 1910 2.2.5. Fluidization of the Cytoplasm 1911 3. The Bacterial Nucleoid 1911 4. Crowding and Phase Separation in Membrane Environments 4.1. Remodeling of the Membrane by Crowding and Phase Separation 4.

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“…Water molecules in the hydration layer of proteins, referred to as biological water, are intimately associated with biomolecular dynamics, oftentimes driving the same, an aspect that has been termed as solvent slaving of motions. , To mimic the cellular environment, researchers have been using polymer-based crowders with sugar (Dextran and Ficoll) and poly ethylene glycol (PEG) as the monomeric units since performing experiments in cellular environments can be quite challenging. Macromolecular crowding, through the excluded volume effect, has been shown to shift the protein folding–unfolding equilibrium toward the native state. − Crowding has also been shown to modulate enzyme activity, − influence conformations of nucleic acids, , play an important role in cellular organization and nuclear architecture, affect structure and dynamics of biological membranes, − enhance extracellular matrix deposition, and alter diffusion properties of molecules. − All these effects have been primarily attributed to the hard sphere repulsive effects, with the latter also having led to the recent development of FRET-based crowding sensors …”

Section: Introductionmentioning

confidence: 99%

Bridging Soft Interaction and Excluded Volume in Crowded Milieu through Subtle Protein Dynamics

Majumdar,

Rastogi,

Chowdhury

2024

J. Phys. Chem. B

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The impact of macromolecular crowding on biological macromolecules has been elucidated through the excluded volume phenomenon and soft interactions. However, it has often been difficult to provide a clear demarcation between the two regions. Here, using temperature-dependent dynamics (local and global) of the multidomain protein human serum albumin (HSA) in the presence of commonly used synthetic crowders (Dextran 40, PEG 8, Ficoll 70, and Dextran 70), we have shown the presence of a transition that serves as a bridge between the soft and hard regimes. The bridging region is independent of the crowder identity and displays no apparent correlation with the critical overlap concentration of the polymeric crowding agents. Moreover, the dynamics of domains I and II and the protein gating motion respond differently, thereby bringing to the fore the asymmetry underlying the crowder influence on HSA. In addition, solvent-coupled and decoupled protein motions indicate the heterogeneity of the dynamic landscape in the crowded milieu. We also propose an intriguing correlation between protein stability and dynamics, with increased global stability being accompanied by eased local domain motion.

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How it feels in a cell

Cited by 17 publications

References 124 publications

Sequence-ensemble-function relationships for disordered proteins in live cells

Sequence-ensemble-function relationships for disordered proteins in live cells

Macromolecular Crowding, Phase Separation, and Homeostasis in the Orchestration of Bacterial Cellular Functions

Bridging Soft Interaction and Excluded Volume in Crowded Milieu through Subtle Protein Dynamics

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