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Related Concept Videos

Amyloid Fibrils03:03

Amyloid Fibrils

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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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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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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Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
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ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations.

Benfeard Williams1, Marino Convertino1, Jhuma Das1

  • 1Biochemistry and Biophysics Department, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.

Plos Computational Biology
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The APOE4 gene variant, a significant Alzheimer's disease (AD) risk factor, exhibits a unique misfolded state. This structural intermediate may explain AD pathogenesis by disrupting cellular pathways and protein clearance.

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Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • The apolipoprotein E (APOE) gene has three variants: E2, E3, and E4, differing by two amino acids.
  • APOE4 is the primary genetic risk factor for Alzheimer's disease (AD), while APOE2 is protective and APOE3 is neutral.
  • The mechanism by which APOE isoforms influence AD risk is thought to involve alterations in protein homeostasis and cellular pathways.

Purpose of the Study:

  • To investigate the structural differences between APOE isoforms.
  • To identify potential molecular mechanisms linking APOE4 to Alzheimer's disease pathogenesis.

Main Methods:

  • Molecular dynamics simulations were employed to analyze the structural behavior of APOE isoforms.
  • Structural modeling was used to characterize the misfolded intermediate state of APOE4.

Main Results:

  • Despite high sequence similarity, only APOE4 demonstrated a misfolded intermediate state with unique domain-domain interactions.
  • This APOE4-specific intermediate may disrupt lipid transport and impair the clearance of AD-related proteins.
  • The first structural model of an APOE4 misfolded intermediate state was generated.

Conclusions:

  • The APOE4 misfolded intermediate state offers a potential molecular explanation for its role in AD pathogenesis.
  • Understanding this structural intermediate provides a basis for developing novel therapeutic strategies against Alzheimer's disease.