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Related Concept Videos

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.
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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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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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Mitochondrial Precursor Proteins01:39

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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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Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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The translocon complex situated on the ER membrane is the main gateway for the protein secretory pathway. It facilitates the transport of nascent peptides into the ER lumen and their insertion into the ER membrane.
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Related Experiment Video

Updated: May 29, 2025

X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
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MIA40 circumvents the folding constraints imposed by TRIAP1 function.

Jordi Pujols1, Marc Fornt-Suñé1, Marcos Gil-García1

  • 1Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i de Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.

The Journal of Biological Chemistry
|February 5, 2025
PubMed
Summary

Mitochondrial import protein MIA40 accelerates TRIAP1 folding by 30-fold, bypassing a kinetic trap. This redox-controlled process is crucial for TRIAP1

Keywords:
MIA40 pathwayTRIAP1disorder-to-order transitionfolding intermediatesmolten globuleoxidative folding

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Area of Science:

  • Mitochondrial protein import and folding.
  • Redox biology and oxidative protein folding.
  • Molecular mechanisms of protein trafficking.

Background:

  • The MIA40 system facilitates the import and oxidative folding of cysteine-rich proteins into the mitochondrial intermembrane space (IMS).
  • TRIAP1, a MIA40 substrate, has dual functions in phospholipid trafficking and apoptosis regulation, with dysregulation linked to oncogenesis.
  • TRIAP1's unique sequence and folding pathway deviate from typical MIA40 substrates, potentially involving a metastable molten globule intermediate.

Purpose of the Study:

  • To investigate the redox-controlled folding pathway of TRIAP1.
  • To elucidate the mechanism by which MIA40 accelerates TRIAP1 folding.
  • To understand the structural constraints and functional implications of TRIAP1's folding pathway.

Main Methods:

  • Studied the folding kinetics and intermediates of TRIAP1.
  • Investigated the role of MIA40 in TRIAP1 oxidation and disulfide bond formation.
  • Analyzed the structural characteristics of TRIAP1's reduced state.

Main Results:

  • In its reduced state, TRIAP1 forms a metastable alpha-helical molten globule, biasing folding towards a non-native kinetic trap.
  • MIA40 accelerates TRIAP1 folding by 30-fold, efficiently bypassing this kinetic trap.
  • MIA40 catalyzes the sequential formation of two disulfide bonds (Cys18-Cys37 and Cys8-Cys47) to achieve the native structure.

Conclusions:

  • TRIAP1's folding pathway is constrained by its IMS function in phospholipid transport.
  • The functional molten globule state of reduced TRIAP1 may link it to p53-dependent cell survival pathways.
  • This study reveals a unique example of a functional molten globule state in mitochondrial protein import.