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Related Concept Videos

Overview of Protein Sorting and Transport01:45

Overview of Protein Sorting and Transport

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Eukaryotic cells have different membrane-bound organelles with distinct protein requirements. The process by which proteins are targeted to a specific organelle is called protein sorting.
Protein sorting can be of two types: signal-based sorting and vesicle-based trafficking. In signal-based sorting, specific amino acid sequences called sorting signals target proteins to the proper location inside the cell either via gated transport or by protein translocation.  In gated transport, folded...
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Post-translational Translocation of Proteins to the RER01:27

Post-translational Translocation of Proteins to the RER

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A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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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
During cotranslational translocation, the Sec61 channel partners with the signal recognition particle (SRP), the signal recognition particle receptor (SR), and the ribosomes to transport the nascent polypeptide chain...
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Directing Proteins to the Rough Endoplasmic Reticulum01:34

Directing Proteins to the Rough Endoplasmic Reticulum

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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Protein Transport to the Thylakoids01:22

Protein Transport to the Thylakoids

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Thylakoids are membrane-bound sac-like structures within the chloroplast that serve as sites for photosynthesis. Thylakoid lumen contains many electron transport proteins and is enclosed by a thylakoid membrane rich in the light-harvesting complex. Proteins targeted to the thylakoids are transported as precursors and are sorted by the general TOC/TIC import pathway. Once the precursor reaches the stroma, stromal processing peptidases remove their transit signal and expose thylakoid signal...
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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Related Experiment Video

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Heterokaryon Technique for Analysis of Cell Type-specific Localization
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Targeted protein relocalization via protein transport coupling.

Christine S C Ng1, Aofei Liu1, Bianxiao Cui1

  • 1Department of Chemistry, Stanford University, Stanford, CA, USA.

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|September 18, 2024
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Summary

Researchers developed targeted relocalization-activating molecules (TRAMs) to control protein localization for disease therapy. TRAMs harness shuttle proteins to rewire cellular interactomes, showing promise in neurodegenerative disease models.

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Area of Science:

  • Cell Biology
  • Molecular Medicine
  • Biochemistry

Background:

  • Subcellular protein localization is crucial for protein function and is often disrupted in diseases like cancer and neurodegeneration.
  • Targeted therapeutic strategies that rewire protein localization to correct disease phenotypes are highly desirable.

Purpose of the Study:

  • To develop and validate targeted relocalization-activating molecules (TRAMs) for controlling subcellular protein localization.
  • To demonstrate the potential of TRAMs in correcting disease-driving protein mislocalization and rewiring cellular interactomes.

Main Methods:

  • Identification of shuttle proteins with suitable ligands for TRAM development.
  • Utilizing a custom imaging analysis pipeline to assess TRAM-induced protein relocalization.
  • Employing nuclear hormone receptors and endogenous proteins as shuttles to redistribute disease-associated proteins.

Main Results:

  • Demonstrated successful modulation of protein steady-state localization by molecularly coupling to shuttle proteins.
  • Showcased TRAM-mediated nuclear relocalization of mutant FUS (FUS^R495X), reducing stress granules in a cellular stress model.
  • Achieved relocalization of endogenous proteins (PRMT9, SOS1, FKBP12) using endogenous shuttle proteins.
  • Showed that small-molecule-induced nuclear-to-axonal redistribution of nicotinamide nucleotide adenylyltransferase 1 slowed axonal degeneration in mice.

Conclusions:

  • Targeted protein relocalization using TRAMs is a viable strategy for therapeutic intervention.
  • This approach offers a novel way to rewire cellular interactomes and address disease mechanisms.
  • The findings open new avenues for developing treatments for neurodegenerative diseases and other conditions characterized by protein mislocalization.