Proprotein convertases (PCs), furin and proprotein convertase 1/3 (PC1), cleave substrates at dibasic residues along the eukaryotic secretory/endocytic pathway. PCs are evolutionarily related to bacterial subtilisin and are synthesized as zymogens. They contain N-terminal propeptides (PRO) that function as dedicated catalysts which facilitate folding and regulate activation of cognate proteases through multiple-ordered cleavages. Previous studies identified a histidine residue (His69) that functions as a pH sensor in the propeptide of furin (PROFUR), which regulates furin activation at pH~6.5 within the trans Golgi network. Although this residue is conserved in the PC1 propeptide (PROPC1), PC1 nonetheless activates at pH~5.5 within the dense core secretory granules. Here we analyze the mechanism by which PROFUR regulates furin activation and examine why PROFUR and PROPC1 differ in their pH-dependent activation. Sequence analyses establish that while both PROFUR and PROPC1 are enriched in histidines when compared with cognate catalytic-domains and prokaryotic orthologs, histidine content in PROFUR is ~two-fold greater than PROPC1, which may augment its pH sensitivity. Spectroscopy and molecular dynamics establish that histidine-protonation significantly unfolds PROFUR when compared to PROPC1 to enhance autoproteolysis. We further demonstrate that PROFUR and PROPC1 are sufficient to confer organelle-sensing on folding and activation of their cognate proteases. Swapping propeptides between furin and PC1 transfers pH-dependent protease activation in a propeptide-dictated manner in vitro and in cells. Since prokaryotes lack organelles and eukaryotic PCs evolved from propeptide-dependent, not propeptide-independent prokaryotic subtilases, our results suggest that histidine enrichment may have enabled propeptides to evolve to exploit pH-gradients to activate within specific organelles.

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Background: Adventure sports events consist of a combination of two or more endurance disciplines, such as orienteering, running, and rock climbing, that range from a day’s to a week’s duration. No studies have examined acute kidney injury (AKI) in adventure sports athletes.Objectives: To describe the prevalence of AKI in participants in the Endeavor Team Challenge, a 30-hour, 40-mile adventure race.Methods: In this prospective observational study, body weights were recorded at race registration. At the finish line, blood sample results by point-of-care testing and weights were recorded. Changes in serum creatinine (Cr) from an estimated baseline value and severity of AKI were calculated, with “risk of injury” defined as 1.5 x baseline Cr, and “injury” defined as 2 x baseline Cr. These two categories of AKI were combined to calculate the total prevalence. Results: There were 88 enrolled study participants with complete data available on 46 (52%). The mean age of those enrolled in the study was 36.8 years (+/- 7.7), 90% were males, and body mass index (BMI) was 25.7 kg/m2 (+/- 2.4). Of the competitors who completed the study, 34 (73%) had some degree of AKI, with 27 (58%) found to be at "risk" and seven (15%) with "injury". There was a significant correlation between weight loss and elevated Cr (r = -0.29, p = 0.047), with a trend towards nonsteroidal anti-inflammatory drug (NSAID) use being correlated with AKI (p = 0.058).Conclusion: Acute kidney injury was observed in the majority of the Endeavor Team Challenge adventure racers, similar to what has been observed in multistage ultramarathons, and greater than after standard marathons and single-stage ultramarathons.

Background: Adventure sports events consist of a combination of two or more endurance disciplines, such as orienteering, running, and rock climbing, that range from a day's to a week's duration. No studies have examined acute kidney injury (AKI) in adventure sports athletes.