The endoplasmic reticulum (ER) provides a specialized environment for the folding of secreted and membrane proteins, a process supported by many different chaperones. Among these chaperones, peptidyl-prolyl cis/trans isomerases (PPIases) catalyze a rate-limiting conformational step in protein folding, yet the principles governing isoform-specific function of PPIases remain poorly defined. Cyclophilin B (CypB), an ER-resident PPIase, has been implicated in early folding events, but whether its activity reflects biochemical adaptation to the ER environment is unclear. Here, we report the biophysical characterization of human CypB and compare it with the cytosolic isoform Cyclophilin A. Spectroscopic and enzymatic analyses show that CypB adopts the canonical cyclophilin fold and displays catalytic activity toward multiple substrates under both cytosolic- and ER-mimicking conditions, indicating that its enzymatic properties are not uniquely tuned to the ER milieu. Confocal imaging confirms that full-length CypB is enriched in the ER, and that removal of its N-terminal segment disrupts this localization. Together, these results indicate that subcellular localization, mediated by an N-terminal membrane anchor, rather than catalytic specialization, may define the physiological role of CypB. Our findings underscore compartmentalization as a central organizing principle of proteostasis in the secretory pathway.
DeVoe et al. (Thu,) studied this question.