Recent advances in understanding catalysis of protein folding by molecular chaperones

Balchin, David; Hayer‐Hartl, Manajit; Hartl, F. Ulrich

doi:10.1002/1873-3468.13844

Cited by 124 publications

(108 citation statements)

References 108 publications

(172 reference statements)

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“…When compared to the N-glycoproteome that represents the total population of potential substrates (4,361 N-glycoproteins in human cells), the UGGTs favored the modification of more complex, multidomain proteins with large numbers of N-glycans. These results are in agreement with the common requirement of chaperones for the proper folding of more complex proteins (Balchin et al, 2016(Balchin et al, , 2020. The lectin chaperone system is part of the robust chaperone network necessary to promote the efficient folding and quality control of substrates and mitigate harmful misfolding events that are associated with a large range of pathologies.…”

Section: Discussionsupporting

confidence: 88%

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Adams

Canniff

Guay

et al. 2020

eLife

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UDP-glucose:glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway, yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from the ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The 71 UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycoproteome. UGGT1 was the dominant glucosyltransferase with a preference toward large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on the carbohydrate-dependent chaperone system to facilitate proper folding and maturation of the cellular N-glycoproteome.

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Section: Discussionsupporting

confidence: 88%

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Adams

Canniff

Guay

et al. 2020

eLife

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“…During biosynthesis, some proteins must overcome energy barriers in order to achieve their native fold (1). For these proteins, interaction with ATP-powered chaperones assists them in attaining a functional conformation on a biologically relevant time scale in vivo (1). This chaperone interaction is not limited to biosynthesis, as changes in intracellular conditions, for example temperature or oxidative stress, or the presence of toxic compounds, can destabilize folding of a wide array of proteins (2)(3)(4), which may then require refolding.…”

Section: Introductionmentioning

confidence: 99%

The chaperonin GroESL facilitatesCaulobacter crescentuscell division by supporting the function of the actin homologue FtsA

Schroeder

Heinrich

Neuwirth

et al. 2020

Preprint

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The highly conserved chaperonin GroESL performs a crucial role in protein folding, however the essential cellular pathways that rely on this chaperone are underexplored. Loss of GroESL leads to severe septation defects in diverse bacteria, suggesting the folding function of GroESL may be integrated with the bacterial cell cycle at the point of cell division. Here, we describe new connections between GroESL and the bacterial cell cycle, using the model organism Caulobacter crescentus. Using a proteomics approach, we identify candidate GroESL client proteins that become insoluble or are degraded specifically when GroESL folding is insufficient, revealing several essential proteins that participate in cell division and peptidoglycan biosynthesis. We demonstrate that other cell cycle events such as DNA replication and chromosome segregation are able to continue when GroESL folding is insufficient, and find that deficiency of the bacterial actin homologue FtsA function mediates the GroESL-dependent block in cell division. Our data suggest that a GroESL-FtsA interaction is required to maintain normal dynamics of the FtsZ scaffold and divisome functionality in C. crescentus. In addition to supporting FtsA function, we show that GroESL is required to maintain the flow of peptidoglycan precursors into the growing cell wall. Linking a chaperone to cell division may be a conserved way to coordinate environmental and internal cues that signal when it is safe to divide.ImportanceAll organisms depend on mechanisms that protect proteins from misfolding and aggregation. GroESL is a highly conserved molecular chaperone that functions to prevent protein aggregation in organisms ranging from bacteria to humans. Despite detailed biochemical understanding of GroESL function, the in vivo pathways that strictly depend on this chaperone remain poorly defined in most species. This study provides new insights into how GroESL is linked to the bacterial cell division machinery, a crucial target of current and future antimicrobial agents. We identify a functional interaction between GroESL and FtsA, a conserved bacterial actin homologue, suggesting that as in eukaryotes, some bacteria exhibit a connection between cytoskeletal actin proteins and chaperonins. Our work further defines how GroESL is integrated with cell wall synthesis, and illustrates how highly conserved folding machines ensure the functioning of fundamental cellular processes during stress.

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mentioning

confidence: 99%

“…During biosynthesis, some proteins must overcome energy barriers in order to achieve their native fold (1). For these proteins, interaction with ATP-powered chaperones assists them in attaining a functional conformation on a biologically relevant time scale in vivo (1). This chaperone interaction is not limited to biosynthesis, as changes in intracellular conditions (e.g., temperature or oxidative stress, or the presence of toxic compounds) can destabilize folding of a wide array of proteins (2)(3)(4), which may then require refolding.…”

mentioning

confidence: 99%

“…The majority of ATP-powered protein folding in prokaryotes is carried out by the highly conserved DnaK/J/GrpE-ClpB bichaperone system and the GroES/EL chaperonin machine (1), which are assisted in interacting with their client proteins by a network of less-conserved holdases, including small heat shock proteins and chaperedoxins (6). GroEL (Hsp60, Cpn60) is a heat shock protein that oligomerizes into a tetradecameric double ring structure with two central cavities that can capture unfolded proteins via their solvent-exposed hydrophobic residues (7).…”

mentioning

confidence: 99%

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The Chaperonin GroESL Facilitates Caulobacter crescentus Cell Division by Supporting the Functions of the Z-Ring Regulators FtsA and FzlA

Schroeder

Heinrich

Neuwirth

et al. 2021

mBio

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The highly conserved chaperonin GroESL performs a crucial role in protein folding; however, the essential cellular pathways that rely on this chaperone are underexplored. Loss of GroESL leads to severe septation defects in diverse bacteria, suggesting the folding function of GroESL may be integrated with the bacterial cell cycle at the point of cell division. Here, we describe new connections between GroESL and the bacterial cell cycle using the model organism Caulobacter crescentus. Using a proteomics approach, we identify candidate GroESL client proteins that become insoluble or are degraded specifically when GroESL folding is insufficient, revealing several essential proteins that participate in cell division and peptidoglycan biosynthesis. We demonstrate that other cell cycle events, such as DNA replication and chromosome segregation, are able to continue when GroESL folding is insufficient. We further find that deficiency of two FtsZ-interacting proteins, the bacterial actin homologue FtsA and the constriction regulator FzlA, mediate the GroESL-dependent block in cell division. Our data show that sufficient GroESL is required to maintain normal dynamics of the FtsZ scaffold and divisome functionality in C. crescentus. In addition to supporting divisome function, we show that GroESL is required to maintain the flow of peptidoglycan precursors into the growing cell wall. Linking a chaperone to cell division may be a conserved way to coordinate environmental and internal cues that signal when it is safe to divide. IMPORTANCE All organisms depend on mechanisms that protect proteins from misfolding and aggregation. GroESL is a highly conserved molecular chaperone that functions to prevent protein aggregation in organisms ranging from bacteria to humans. Despite detailed biochemical understanding of GroESL function, the in vivo pathways that strictly depend on this chaperone remain poorly defined in most species. This study provides new insights into how GroESL is linked to the bacterial cell division machinery, a crucial target of current and future antimicrobial agents. We identify a functional interaction between GroESL and the cell division proteins FzlA and FtsA, which modulate Z-ring function. FtsA is a conserved bacterial actin homologue, suggesting that as in eukaryotes, some bacteria exhibit a connection between cytoskeletal actin proteins and chaperonins. Our work further defines how GroESL is integrated with cell wall synthesis and illustrates how highly conserved folding machines ensure the functioning of fundamental cellular processes during stress.

show abstract

Recent advances in understanding catalysis of protein folding by molecular chaperones

Cited by 124 publications

References 108 publications

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

The chaperonin GroESL facilitatesCaulobacter crescentuscell division by supporting the function of the actin homologue FtsA

The Chaperonin GroESL Facilitates Caulobacter crescentus Cell Division by Supporting the Functions of the Z-Ring Regulators FtsA and FzlA

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