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Related Concept Videos

Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Assembly of Signaling Complexes01:30

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites...
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Translocation of Proteins into the Mitochondria01:19

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Protein Transport into the Inner Mitochondrial Membrane01:34

Protein Transport into the Inner Mitochondrial Membrane

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Nuclear encoded mitochondrial precursors are imported to the inner membrane in a multistep process involving two separate translocons, TIM22 and TIM23. TIM23 is a cation-selective pore that remains closed by the N terminal segment of the protein. Negative charges on the TIM23 act as a receptor for the incoming precursor, pulling the positively charged matrix-targeting sequence for peptide insertion and translocation.
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Mitochondrial Protein Sorting01:39

Mitochondrial Protein Sorting

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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death.  Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
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In Situ Detection of Ribonucleoprotein Complex Assembly in the C. elegans Germline using Proximity Ligation Assay
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Structural insights into metazoan pretargeting GET complexes.

Alexander F A Keszei1, Matthew C J Yip1, Ta-Chien Hsieh1,2

  • 1Department of Cell Biology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.

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|December 10, 2021
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Chaperones coordinate tail-anchored protein delivery to the ER. Cryo-EM structures reveal how the pretargeting complex primes Get3 for efficient client loading and targeting.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Structural Biology

Background:

  • Chaperone proteins are crucial for protein biosynthesis and cellular function.
  • Tail-anchored (TA) proteins require specific pathways for targeting to the endoplasmic reticulum (ER).
  • The Guided Entry of TA proteins (GET) pathway ensures correct protein localization.

Purpose of the Study:

  • To elucidate the structural mechanisms of the metazoan pretargeting GET complex.
  • To understand how chaperones coordinate the loading of TA proteins onto the Get3 ATPase.
  • To reveal the structural basis for efficient TA protein transfer and ER targeting.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) at 3.3-3.6 Å resolution.
  • Structural analysis of metazoan pretargeting GET complexes.
  • Biochemical assays to study protein-protein interactions and transfer reactions.

Main Results:

  • Determined high-resolution cryo-EM structures of the pretargeting GET complex.
  • Revealed Get3 helix 8 and Get4 C-terminus form a composite lid, opened by SGTA.
  • Identified Get4 interactions that regulate Get3 conformation, facilitating TA protein transfer from SGTA to Get3.

Conclusions:

  • The pretargeting complex dynamically regulates Get3 conformation.
  • SGTA and Get4 act as key regulators in the TA protein transfer process.
  • The findings provide a structural framework for understanding Get3 client loading and ER targeting.