Paola Bisignano

1 week ago | biorxiv.org | Andrew Rice |Mayuresh G Gadgil |Paola Bisignano |Richard Stein

AbstractAmino acids undergo numerous enzymatic modifications. However, the broad applicability of amino acid-modifying enzymes for synthetic purposes is limited by narrow substrate scope and often unknown regulatory or accessory factor requirements. Here, we characterize ChlH, a flavin-dependent halogenase (FDH) from the chlorolassin biosynthetic gene cluster.

Jul 31, 2024 | nature.com | Nadine Mundt-Machado |Paola Bisignano |Gabriel B. Loeb |Jeremy F. Reiter |Erhu Cao |Markus Delling | +2 more

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC–dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics. It is currently unknown how environmental cues regulate ciliary Polycystin ion channels on renal epithelial cells. Here authors identify a cilia-enriched oxysterol, 7β,27- dihydroxycholesterol (DHC), as a necessary activator of the polycystin complex