Mechanism of Fine-tuning pH Sensors in Proprotein Convertases

Williamson, Danielle M.; Elferich, Johannes; Shinde, Ujwal

doi:10.1074/jbc.m115.665430

Cited by 13 publications

(12 citation statements)

References 59 publications

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“…On the other hand, carboxyterminal processing of PC1/3-E345A was severely impaired. Although both processes are autocatalytic, propeptide cleavage is an intramolecular process and carboxyterminal processing is intermolecular, which follow different kinetics [ 26 , 27 , 28 , 29 ]. Consistently, we did not detect cleavage activity when using a substrate in trans, confirming that this mutant form was catalytically inert ( Figure 2 C).…”

Section: Resultsmentioning

confidence: 99%

“…Although the E345A mutant does not cleave substrates in trans, this mutation did not exert any effect on the maturation and secretion of the enzyme, suggesting normal autocatalytic activation. The prodomain of proPC1/3 is cleaved in a rapid intramolecular way at the primary site RSKR110 (t 1/2 < 2 min) and after it enters the more acidic Golgi compartments, at the second cleavage site RRSRR 81 [ 26 , 27 , 28 , 29 ]. In our in vitro assay, we showed normal cleavage and subcellular trafficking.…”

Section: Discussionmentioning

confidence: 99%

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Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Aerts

Terry

Sainath

et al. 2021

Genes

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Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Aerts

Terry

Sainath

et al. 2021

Genes

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“…An earlier paper by Feliciangeli et al [ 87 ] identified a pH sensor in the furin pro-peptide that regulates enzyme activation and showed that furin activation occurs in the endoplasmic reticulum, and that furin has a conserved histidine that acts as a pH sensor. In support, Williamson et al [ 30 ] further concluded that “Different spatial distributions of histidine residues modulate the activation pH of pro-protein convertases”, such as furin. Noted is also that furin may seek a specific amino acid sequence for cleavage supporting Coutard’s et al report [ 33 ].…”

Section: Phmentioning

confidence: 95%

“…The structure of furin has both an amino group and a carboxylic acid group but a net neutral charge, which plausibly allows ‘zwitterionic’ or dipolar-like behavior and functions. It is known that for furin action in various organelle sites requires an acidic pH [ 30 ]. The TMPRSS2 serine host protease in the receptor site of CV19 is acidic and hence a welcome partner for furin action.…”

Section: Furinmentioning

confidence: 99%

Does Covera-19 know ‘when to hold ‘em or ‘when to fold ‘em? A translational thought experiment

Griffin

2021

transl med commun

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The function of proteins depends on their structure. The structural integrity of proteins is dynamic and depends on interacting nearby neighboring moieties that influence their properties and induce folding and structural changes. The conformational changes induced by these nearby neighbors in the micro-environmental milieu at that moment are guided by chemical or electrical bonding attractions.There are few literature references that describe the potential for environmental milieu changes to disfavor SARS-CoV-2 attachment to a receptor for survival outside of a host. There are many studies on the effects of pH (acid and base balance) supporting its importance for protein structure and function, but few focus on pH role in extracellular or intracellular protein or actionable requirements of Covera-19.‘Fold ‘em or Hold ‘em’ is seen by the various functions and effects of furin as it seeks an acidic milieu for action or compatible amino acid sequences which is currently aided by its histidine component and the structural changes of proteins as they enter or exit the host. Questions throughout the text are posed to focus on current thoughts as reviewing applicable COVID-19 translational research science in order to understand the complexities of Covid-19.The pH needs of COVID-19 players and its journey through the human host and environment as well as some efficacious readily available repurposed drugs and out-of-the box and easily available treatments are reviewed.

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“…Histidine residues are often situated within functionally important sites of proteins, where their protonation status dictates the protein's functionality [30][31][32] . The protonation state of histidine residues also regulates the activity of particular cell-surface receptors and transporters, such as G-coupled receptors 33 and ion transporters 34,35 .…”

Section: Introductionmentioning

confidence: 99%

Evolution of pH-sensitive transcription termination during adaptation to repeated long-term starvation

Worthan,

McCarthy,

Delaleau

et al. 2024

Preprint

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Fluctuating environments that consist of regular cycles of co-occurring stress are a common challenge faced by cellular populations. For a population to thrive in constantly changing conditions, an ability to coordinate a rapid cellular response is essential. Here, we identify a mutation conferring an arginine-to-histidine (Arg to His) substitution in the transcription terminator Rho. TherhoR109H mutation frequently arose inE. colipopulations experimentally evolved under repeated long-term starvation conditions, during which feast and famine result in drastic environmental pH fluctuations. Metagenomic sequencing revealed that populations containing the rho mutation also possess putative loss-of-function mutations inydcI, which encodes a recently characterized transcription factor associated with pH homeostasis. Genetic reconstructions of these mutations show that therhoallele confers a plastic alkaline-induced reduction of Rho function that, when found in tandem with aΔydcIallele, leads to intracellular alkalinization and genetic assimilation of Rho mutant function. We further identify Arg to His substitutions at analogous sites inrhoalleles from species originating from fluctuating alkaline environments. Our results suggest that Arg to His substitutions in global regulators of gene expression can serve to rapidly coordinate complex responses through pH sensing and shed light on how cellular populations across the tree of life use environmental cues to coordinate rapid responses to complex, fluctuating environments.

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Mechanism of Fine-tuning pH Sensors in Proprotein Convertases

Cited by 13 publications

References 59 publications

Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Does Covera-19 know ‘when to hold ‘em or ‘when to fold ‘em? A translational thought experiment

Evolution of pH-sensitive transcription termination during adaptation to repeated long-term starvation

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