Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites

Abstract

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Control of CCR5 Cell-Surface Targeting by the PRAF2 Gatekeeper

“…PRAF2 has been reported to play the role of gatekeeper [31], capable of physiologically retaining, on a stoichiometric basis, wild-type GBR1 and CFTR in the ER [20,21]. The possible control of CCR5 export by PRAF2 was investigated by measuring the amount of CCR5 reaching the cell surface in the presence of increasing concentrations of PRAF2 with the biosensor used above (Figure 2C).…”

“…Since PRAF2 was originally identified as an interacting partner of the C-terminal tail of CCR5 [22], which is absent in the CCR5-ΔCter mutant, additional domain(s) of interaction with PRAF2 likely exist in the CCR5 sequence. In particular, PRAF2 was reported to interact with tandem LL RXR motifs present in the GB1 C-terminal tail [20] and in the CFTR nucleotide-binding domain, NBD1 [21]. Similar motifs appear in the third intracellular loop (I3) of CCR5.…”

“…PRAF2 was subsequently found to interact with both wild-type and mutant cystic fibrosis (CF) transmembrane conductance regulator (CFTR) on a stoichiometric basis, preventing the access of newly synthesized cargo to ERESs. The PRAF2-CFTR interaction involves a specific RXR-di-leucine motif located in the first nucleotide-binding domain of the transporter [21].…”

Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

“…in PKU, cystic fibrosis, and lysosomal storage disorders. [38][39][40] Therefore, small molecule compounds that can stabilize TH protein and increase TH activity in vitro and in vivo appear relevant for THD treatment as alternatives or supplements to L-Dopa. Here we show that in the DSF assays BH 4 and its inactive analog BH 2 exhibited a low but significant ΔT m increase (1.1 ± 0.1) at low concentration in the case of BH 4 (10 μM), and higher with BH 2 (62.4 μM), due to its lower affinity for TH than BH 4.…”

“…The concept of developing therapies based on pharmacological chaperones has been explored in various inborn errors of metabolism, especially if the main pathological mechanism is the variant‐associated protein instability and misfolding, such as e.g. in PKU, cystic fibrosis, and lysosomal storage disorders 38–40 . Therefore, small molecule compounds that can stabilize TH protein and increase TH activity in vitro and in vivo appear relevant for THD treatment as alternatives or supplements to L‐Dopa.…”