How Long to Read Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control

How Long Does it Take to Read Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control?

It takes the average reader 8 hours and 30 minutes to read Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control by Sharma, Manu

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Description

The consensus is that the Phe508 deletion (DeltaF508), the most common c & barbelow;ystic f & barbelow;ibrosis (CF) mutation, imposes a temperature-sensitive folding defect on the CF t & barbelow;ransmembrane conductance r & barbelow;egulator (CFTR), a CAMP-regulated chloride channel at the apical epithelial membrane. The incompletely folded DeltaF508CFTR is targeted for degradation by ER-associated degradation (ERAD). Limited CFTR activity, however, has been reported at the cell surface in epithelia of homozygous DeltaF508CFTR mice and patients, suggesting that the ER-retention of the mutant is incomplete. To elucidate the reasons behind the inability of DeltaF508 CFTR to accumulate at the plasma membrane, its stability and cellular fate were determined following release from ER. Biochemical and functional measurements revealed that rescued DeltaF508 (rDeltaF508) CFTR has a temperature-sensitive stability defect in post-Golgi compartments. The>4--20 fold accelerated degradation between 37--40°C, is likely due to reduced conformational stability of the rDeltaF508CFTR; demonstrated by SDS-resistant thermo-aggregation and in situ protease susceptibility. We propose that the structural and metabolic instability of the rDeltaF508CFTR, confirmed in human primary respiratory and pancreatic epithelia, contribute to its inability to accumulate at the cell surface. Degradation mechanism of the misfolded membrane proteins (e.g. mutant CFTR) in the post-Golgi compartments, is not known. To investigate this process, we used two pathogenic mutants (DeltaF508CFTR and Delta70CFTR) exhibiting conformational instability in the post-Golgi compartments. The folding state of these CFTR mutants determined the endocytic trafficking of the constitutively internalized channels. We demonstrated that native CFTR recycles from sorting endosomes to the cell surface, while misfolding due to thermosensitive mutations prevents recycling and targets the channels to lysosomal degradation by promoting their ubiquitination. Rescuing the folding defect or downregulating the E1 Ub-activating enzyme stabilized the mutant CFTR, without interfering with its constitutive internalization. These and other observations, in concert with the preferential association of mutant CFTR with the components of Ub-dependent endosomal sorting machinery, revealed a link between Ub-modification and lysosomal degradation of misfolded CFTR from the cell surface. This work not only provides evidence for a novel cellular mechanism of CF pathogenesis, but also suggests a paradigm for the post-Golgi quality control of membrane proteins involving ubiquitination and Ub-dependent endosomal sorting.

How long is Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control?

Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control by Sharma, Manu is 510 pages long, and a total of 127,500 words.

This makes it 172% the length of the average book. It also has 156% more words than the average book.

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The average oral reading speed is 183 words per minute. This means it takes 11 hours and 36 minutes to read Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control aloud.

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Elimination Mechanism of Misfolded CFTR from Post-Golgi Compartments [microform] : a Possible Paradigm of Peripheral Protein Quality Control is suitable for students ages 12 and up.

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