ABCMdb

PMID: 21421917

Balch WE, Roth DM, Hutt DM
Emergent properties of proteostasis in managing cystic fibrosis.
Cold Spring Harb Perspect Biol. 2011 Feb 1;3(2). pii: a004499. doi: 10.1101/cshperspect.a004499., [PubMed]

Sentences

No. Mutations Sentence Comment

38 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Proteostasis in Managing Cystic Fibrosis Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004499 3 Cold Spring Harbor Laboratory Press at SEMMELWEIS UNIV OF MEDICINE on December 5, corrector activity PC/PR potentiator activity PC/PR ER Golgi Lysosome Endosomes Native structure Native structure Apical surface C B SDS-PAGE ƊF508 ƊF508 Ɗ F 5 0 8 w t ERAD Wild-type WT A G551D (NBD1)/G1349D (NBD2) traffic to cell surface but lack channel activity RCN P23 HSTF1 HSP47 HSPA1L CYPB PPIA COC37 HOP Hsp40 HSP70 CFTR HSP90 Core B CANX CHIP CCT3 CCT4 USP49 GRP75 CCT5 CCT1 DNAJA2 BAG1 HSP60 HSP105 HSP21 HSP22 BAG2 RCN2 BAG2 HSC70 GRP78 UBC UBB Aha1 Regulatory Figure 3. Login to comment 40 ABCC7 p.Gly1349Asp (A) Illustrated is the trafficking itinerary of WTand three vCFTR (DF508, G551E, G1349D) through the exocytic pathway. Login to comment 47 ABCC7 p.Gly1349Asp ABCC7 p.Gly551Glu The G551E and G1349D mutants (purple) are folded and traffic normally to cell surface. Login to comment 49 ABCC7 p.Gly1349Asp ABCC7 p.Gly551Glu The G551E and G1349D vCFTR only require a potentiator to open the channel and restore function. Login to comment 105 ABCC7 p.Gly551Asp Importantly, the potentiator drug Vertex 770 (http://www.cff.org/research/ClinicalResearch/ FAQs/VX-770/) (Caputo et al. 2009; Van Goor et al. 2009; Wellhauser et al. 2009; Moran 2010) has recently completed a Phase II clinical trial with the G551D mutant (Fig. 3A), which is trafficked from the ER normally, cell surface localized but lacks channel activity. Login to comment 145 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Moreover, a recent comparison of 13 potentiators showed that three different mutants, including DF508 (NBD1, ER degraded, Fig. 3A), G551D (NBD1, cell surface localized, Fig. 3A), and G1349D (NBD2, cell surface localized) (Pedemonte et al. 2010), expressed in FRT cells or the human alveolar epithelial cells A549 responded to 10 of the 13 compounds tested, supporting the conclusion that these potentiators may be binding to vCFTR directly and their binding is not influenced by cellular environment (Pedemonte et al. 2010). Login to comment