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Related Concept Videos

Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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ER Retrieval Pathway01:45

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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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Insertion of Multi-pass Transmembrane Proteins in the RER01:29

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The rough ER membrane synthesizes, assembles, and embeds transmembrane proteins in diverse topologies. These proteins function as transporters or channels and can remain in the ER membrane or are sent to the Golgi complex, lysosome, and cell membrane.
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Insertion of Single-pass Transmembrane Proteins in the RER01:26

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Integral membrane proteins are proteins adhered to the lipid bilayer of a cell organelle or membrane. They can be of two types: transmembrane integral proteins that span the lipid bilayer and monotopic proteins that are attached to either side of the membrane but do not pass through it.
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Protein Folding Quality Check in the RER01:29

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Cotranslational Protein Translocation01:20

Cotranslational Protein Translocation

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Translocation of proteins across membranes is an ancient process that occurs even in bacteria and archaebacteria. In fact, the components of the translocation machinery are still conserved between prokaryotes and eukaryotes.
Sec61 channel partners for cotranslational translocation
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Analysis of Protein Folding, Transport, and Degradation in Living Cells by Radioactive Pulse Chase
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Acting on the CFTR Membrane-Spanning Domains Interface Rescues Some Misfolded Mutants.

Nesrine Baatallah1, Ahmad Elbahnsi2, Benoit Chevalier1

  • 1INSERM, U1151, Institut Necker Enfants Malades (INEM), Faculté de Médecine, Université Paris Cité, CNRS, UMR 8253, 75015 Paris, France.

International Journal of Molecular Sciences
|December 23, 2022
PubMed
Summary

A new mutation partially rescues folding defects in cystic fibrosis transmembrane conductance regulator (CFTR) protein's membrane-spanning domains. This finding offers insights into ABC transporter assembly and function.

Keywords:
ABC transporterABCBABCCCFTRcystic fibrosismolecular dynamicspharmaco-chaperonestructure function relationships

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • ABC transporters feature two nucleotide-binding domains (NBDs) and two membrane-spanning domains (MSDs).
  • Mutations in these domains can impair protein folding and assembly, as seen in cystic fibrosis transmembrane conductance regulator (CFTR).
  • A specific groove in CFTR's MSD1 is implicated in folding defects and drug binding, differing structurally from related ABCB transporters.

Purpose of the Study:

  • To investigate the impact of a second-site mutation near the CFTR MSD1 groove on protein folding.
  • To understand how this mutation affects folding defects caused by other mutations.
  • To explore the structural implications of the mutation on ABC transporter assembly.

Main Methods:

  • Site-directed mutagenesis to introduce a second-site mutation in MSD1.
  • Assessment of the mutation's effect on folding defects caused by known CFTR mutations.
  • 3D structural modeling to analyze protein assembly.

Main Results:

  • A novel MSD1 mutation partially rescued folding defects associated with specific MSD1 mutations.
  • The identified mutation did not rescue the F508del mutation in NBD1.
  • Structural modeling suggested enhanced interactions between MSD1 and MSD2, improving assembly.

Conclusions:

  • The study identified a mutation that partially restores CFTR folding, highlighting the importance of the MSD1 groove.
  • Findings provide insights into the assembly mechanisms of type IV ABC transporters.
  • This research contributes to understanding CFTR protein folding and function, relevant for cystic fibrosis.