Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis

Abstract

G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D 3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.

The molecular sociology of NHERF1 PDZ proteins controlling renal hormone-regulated phosphate transport

“…The published studies disclosed that the binding of the C-terminal motif of PTHR to NHERF1 involves regions outside the canonical core-binding PDZ boundaries [ 35 ]. The molecular determinants beyond the canonical binding site disclose a distinct electrostatic network playing a specific role in recognizing the PTHR C-terminus by the PDZ domains of SNX27 [ 84 ] and Scribble [ 85 ]. Currently, there is no information about the exact site of NHERF1 modification or the effect of phosphorylation by PKA.…”