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Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.

ABSTRACT: The propeptides of proprotein convertases (PCs) regulate activation of cognate protease domains by sensing pH of their organellar compartments as they transit the secretory pathway. Earlier experimental work identified a conserved histidine-encoded pH sensor within the propeptide of the canonical PC, furin. To date, whether protonation of this conserved histidine is solely responsible for PC activation has remained unclear because of the observation that various PC paralogues are activated at different organellar pH values. To ascertain additional determinants of PC activation, we analyzed PC1/3, a paralogue of furin that is activated at a pH of ?5.4. Using biophysical, biochemical, and cell-based methods, we mimicked the protonation status of various histidines within the propeptide of PC1/3 and examined how such alterations can modulate pH-dependent protease activation. Our results indicate that whereas the conserved histidine plays a crucial role in pH sensing and activation of this protease an additional histidine acts as a "gatekeeper" that fine-tunes the sensitivity of the PC1/3 propeptide to facilitate the release inhibition at higher proton concentrations when compared with furin. Coupled with earlier analyses that highlighted the enrichment of the amino acid histidine within propeptides of secreted eukaryotic proteases, our work elucidates how secreted proteases have evolved to exploit the pH of the secretory pathway by altering the spatial juxtaposition of titratable groups to regulate their activity in a spatiotemporal fashion.

SUBMITTER: Williamson DM

PROVIDER: S-EPMC4645620 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.

Williamson Danielle M DM Elferich Johannes J Shinde Ujwal U

The Journal of biological chemistry 20150730 38

The propeptides of proprotein convertases (PCs) regulate activation of cognate protease domains by sensing pH of their organellar compartments as they transit the secretory pathway. Earlier experimental work identified a conserved histidine-encoded pH sensor within the propeptide of the canonical PC, furin. To date, whether protonation of this conserved histidine is solely responsible for PC activation has remained unclear because of the observation that various PC paralogues are activated at di ...[more]

PMID: 26229104

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Project description:Proprotein convertases (PCs), also known as eukaryotic subtilases, are a group of serine proteases comprising furin (PACE), PC1 (PC3), PC2, PC4, PACE4, PC5 (PC6), and PC7 (LPC, PC8) that generate bioactive proteins and peptides, such as hormones, receptors, and growth factors by cleaving precursor proteins at multibasic motifs. Two other family members, SKI-1/S1P and PCSK9, cleave regulator proteins involved in cholesterol and fatty acid homeostasis at nonbasic peptide bonds. Furin is ubiquitous in eukaryotic tissues and cells. PACE4, PC5, and PC7 are also widespread, whereas the expression of the other PCs is more restricted. PCs are synthesized as multi-segmented zymogens which are autocatalytically activated. The prodomains have regulatory and inhibitory functions. The catalytic domains are the most conserved domains among the PCs. The architecture of the catalytic active furin domain is known in different binding states. The C-terminal parts of the PCs differ in length and structure and contain encoded peptide signatures guiding the PCs to the subcellular destinations on the secretory pathways: SKI-1/S1P to the cis-Golgi, furin, PC5B, and PC7 to the TGN region but also to the plasma membrane. PACE4, PC5A, and PCSK9 are attached at the cell surface. Truncated, soluble furin and SKI-1/S1P, as well as PC1 and PC2, are released into the extracellular matrix. Many enveloped viruses are activated by furin and furin-like PCs and arenaviruses and a few bunyaviruses by SKI-1/S1P. The PCs cleave the viral fusion glycoprotein to trigger fusion of viral envelopes with cellular membranes to deliver the viral genome into host cells. Cleavage by PCs, occasionally in concert with other endoproteases, enables conformational changes in the viral membrane proteins needed for correct oligomerization of glycoprotein spikes and their effective incorporation into virions. Mutational alterations of PC cleavage sites can reduce the fusion potential of viral surface proteins and thus facilitate the development of secure live attenuated vaccines. Alternatively, agents preventing cleavage of viral surface (glyco)proteins block fusion capacity and multicyclic virus replications. PC inhibitors are suggested as promising antiviral drugs for quite a number of viruses causing severe infections.

Dataset Information

Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.

Publications

Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.

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