Related Experiment Video

Updated: Apr 17, 2026

Purification of Hsp104, a Protein Disaggregase
07:17

Purification of Hsp104, a Protein Disaggregase

Published on: September 30, 2011

17.9K

Evolutionary conserved Tyr169 stabilizes the β2-α2 loop of the prion protein

Danzhi Huang1, Amedeo Caflisch

  • 1Department of Biochemistry University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Journal of the American Chemical Society
|February 12, 2015
PubMed

Insights

The prion protein's β2-α2 loop structure is key to its conversion. A specific mutation (Y169G) lowers the energy barrier for this loop transition, impacting prion aggregation.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Dynamics

Background:

  • Mammalian prion proteins (PrP) exist as cellular (PrP(C)) and misfolded, aggregated forms.
  • The β2-α2 loop region (residues 165-175) is implicated in the conversion process.
  • Understanding loop dynamics is crucial for prion disease mechanisms.

Purpose of the Study:

  • To investigate the structural transition of the prion protein's β2-α2 loop.
  • To determine the energetic landscape of the loop transition in wild-type and mutant prion proteins.
  • To elucidate the role of tyrosine 169 in stabilizing the native prion protein conformation.

Main Methods:

  • Unbiased molecular dynamics simulations of a Y169G single-point mutant prion protein.
  • Free energy surface sampling using multiple conformations from simulations.
  • Determination of free energy profiles using two distinct computational methods.

Main Results:

  • The Y169G mutation significantly lowers the energy barrier for the β2-α2 loop transition from a 310-helical to a β turn by approximately 2.5 kcal/mol.
  • Favorable aromatic ring stacking between Y169 and F175, and a stable hydrogen bond between Y169 and D178 stabilize the wild-type 310-helical conformation.
  • The loop transition to a β turn exposes a hydrophobic region (residues 169-YSNQNNF-175) to solvent.

Conclusions:

  • The conserved tyrosine at residue 169 (Y169) plays a critical role in stabilizing the 310-helical turn within the β2-α2 loop of mammalian prion proteins.
  • This stabilization by Y169 actively hinders the loop's transition to a β turn, thereby preventing the adoption of an aggregation-prone conformation.
  • The findings provide molecular insights into the structural determinants of prion protein conversion and aggregation.

More Related Videos

Purification and Refolding to Amyloid Fibrils of His6-tagged Recombinant Shadoo Protein Expressed as Inclusion Bodies in E. coli09:43

Purification and Refolding to Amyloid Fibrils of His6-tagged Recombinant Shadoo Protein Expressed as Inclusion Bodies in E. coli

Published on: December 19, 2015

14.9K
Screening for Amyloid Aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis10:03

Screening for Amyloid Aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis

Published on: July 16, 2008

28.8K

Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
5.3K
Conserved Binding Sites01:49

Conserved Binding Sites

2.0K
Amyloid Fibrils03:03

Amyloid Fibrils

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. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining,...
13.2K
Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

Protein domains are small structurally independent units that are part of a single amino acid chain.  Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
15.2K
Conservation of Protein Domains02:26

Conservation of Protein Domains

4.4K
Protein Folding01:25

Protein Folding

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.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
12.7K