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The most common form of CF occurs in response to loss of phenylalanine 508 (F508) in CFTR, resulting in a failure to be exported from the ER. F508 deletion leads to protein misfolding and ER-associated degradation (ERAD). Many groups thus hope to interfere with ERAD to treat CF. But Wang et al. find that the solution may lie elsewhere. "We don't think less degradation," says group leader William Balch. "We think more export."
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Export to the Golgi is required for CFTR to get to its functional location on the cell surface. The authors find that this export relies on a conserved di-acidic motif that must be properly presented to Sec24, a component of the COPII coat.7 f& l* \9 l6 B; G$ r. B, S8 N
5 G% B& E: N1 |( d+ y+ dCFTR with mutations in the di-acidic motif were not exported and were less likely to associate with Sec24 in vivo. Recent crystal structures show that F508 lies in a domain adjacent to the di-acidic motif; the loss of F508 and the resulting misfolding may thus hide the sorting motif from Sec24.2 S7 \! r! ]# r _
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Promising small molecule drug candidates for CF might be selected by their ability to improve interactions between Sec24 and the CFTR domain that contains the di-acidic motif. Blocking ERAD, in contrast, may only lead to ER-trapped CFTR, which could trigger ER stress responses.(Cystic fibrosis (CF) often results from ) |
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发表于 2009-3-6 08:12
发表于 2015-6-3 20:58
