Enhanced sampling molecular dynamics identifies PrP(Sc) structures harboring a C-terminal β-core.
Pascal Baillod1, Julian Garrec, Maria-Carola Colombo
1Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Biochemistry
|November 21, 2012
Summary
This study reveals the C-terminal region of mouse prion protein (PrP) forms beta-rich structures. These findings challenge existing models and propose new structural insights into prion protein precursors.
Area of Science:
- Biophysics
- Structural Biology
- Neuroscience
Background:
- Prion diseases are linked to misfolded prion proteins (PrP).
- The structural basis of prion protein misfolding, particularly the scrapie isoform (PrP(Sc)), remains incompletely understood.
- Existing models propose different structural cores for PrP(Sc).
Purpose of the Study:
- To extensively sample the conformational space of the C-terminal domain of mouse prion protein (PrP).
- To identify and characterize beta-rich structures and folds within this domain.
- To propose novel structural models for prion protein precursors and oligomers.
Main Methods:
- Replica exchange molecular dynamics simulations (2.8 μs total time).
- Enhanced sampling techniques to explore conformational space.
- Clustering algorithms to classify beta-rich conformations.
- Analysis of fold topology, accumulation temperatures, and structural characteristics.
Main Results:
- Identified 1.3% of sampled conformations with high beta-structure content (≥19 residues).
- Assessed beta-propensities and identified structurally labile regions.
- Defined and analyzed ten distinct beta-rich folds.
- Proposed structural models featuring a C-terminal beta-rich core for PrP(Sc) precursors and beta-oligomers.
Conclusions:
- The C-terminal domain of PrP plays a crucial role in forming beta-rich structures.
- Findings contradict models suggesting an N-terminal or central beta-rich core for PrP(Sc).
- The proposed C-terminal beta-rich core model aligns with recent experimental observations.
Related Concept Videos
01:34Directing Proteins to the Rough Endoplasmic Reticulum
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...
01:56Structural Protein Function
Structural proteins are a category of proteins responsible for functions ranging from cell shape and movement to providing support to major structures such as bones, cartilage, hair, and muscles. This group includes proteins such as collagen, actin, myosin, and keratin.
Collagen, the most abundant protein in mammals, is found throughout the body. In connective tissue, such as skin, ligaments, and tendons, it provides tensile strength and elasticity. In bones and teeth, it mineralizes to form...
Collagen, the most abundant protein in mammals, is found throughout the body. In connective tissue, such as skin, ligaments, and tendons, it provides tensile strength and elasticity. In bones and teeth, it mineralizes to form...
01:56Structural Protein Function
Structural proteins are a category of proteins responsible for functions ranging from cell shape and movement to providing support to major structures such as bones, cartilage, hair, and muscles. This group includes proteins such as collagen, actin, myosin, and keratin.
Collagen, the most abundant protein in mammals, is found throughout the body. In connective tissue, such as skin, ligaments, and tendons, it provides tensile strength and elasticity. In bones and teeth, it mineralizes to form...
Collagen, the most abundant protein in mammals, is found throughout the body. In connective tissue, such as skin, ligaments, and tendons, it provides tensile strength and elasticity. In bones and teeth, it mineralizes to form...
01:24Protein Organization
Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular transport, catalysis, and structural support. Proteins have a hierarchical structure comprising at least three levels of organization: primary, secondary, and tertiary structure. Some large proteins have a quaternary structure where individual protein subunits are linked together.
The primary structure of a protein is its amino acid sequence.
The primary structure of a protein is its amino acid sequence.