Related Experiment Video
Updated: Jan 25, 2026
08:40
Millisecond Hydrogen/Deuterium-Exchange Mass Spectrometry for the Study of Alpha-Synuclein Structural Dynamics Under Physiological Conditions
Published on: June 23, 2022
3.5K
Structural determinants of PLD2 inhibition by alpha-synuclein
Jacqueline E Payton1, Richard J Perrin, Wendy S Woods
1Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801, USA.
Journal of Molecular Biology
|March 23, 2004
Summary
Alpha-synuclein and its isoforms inhibit phospholipase D2 (PLD2). This inhibition, crucial for neuronal function and Parkinson
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alpha-synuclein's role in neuronal plasticity and neurodegeneration is unclear.
- Lipid binding may stabilize alpha-synuclein's active alpha-helical conformation.
- Synucleins are known to inhibit phospholipase D (PLD), impacting lipid signaling and vesicle trafficking.
Purpose of the Study:
- To investigate the inhibitory effects of synuclein isoforms and Parkinson's disease (PD)-associated mutants on PLD2.
- To identify the structural determinants within alpha-synuclein responsible for PLD2 inhibition.
- To explore the role of post-translational modifications, such as phosphorylation, in modulating PLD2 inhibition.
Main Methods:
- In vitro assays to measure PLD2 inhibition by wild-type and mutant synucleins.
- Site-directed mutagenesis and deletion analysis of alpha-synuclein to map inhibitory regions.
- Analysis of phosphorylation effects on PLD2 inhibition using specific mutants.
Main Results:
- All three synuclein isoforms (alpha, beta, gamma) and the A30P mutant effectively inhibit PLD2 in vitro.
- The PD-associated A53T mutant exhibits enhanced PLD2 inhibition compared to wild-type alpha-synuclein.
- Exon 4 (residues 56-102), requiring an alpha-helical structure, and exon 6 (residues 130-140) are critical for PLD2 inhibition.
- Phosphorylation at Ser129, Tyr125, or Tyr136 significantly blocks PLD2 inhibition.
Conclusions:
- PLD2 inhibition by alpha-synuclein is mediated by a lipid-stabilized alpha-helix in exon 4 and residues in exon 6.
- The activity of alpha-synuclein as a PLD2 inhibitor can be modulated by phosphorylation at specific sites.
- These findings provide insights into alpha-synuclein's function and its potential role in neurodegenerative diseases like Parkinson's.
Related Concept Videos
01:30Enzyme Inhibition
91.8K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
91.8K
00:46Feedback Inhibition
57.0K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.0K
03:38Structure of Lipids
98.5K
Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon-carbon or carbon-hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals. For example, they help keep aquatic...
98.5K
02:34Inhibition of Cdk Activity
5.8K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.8K
01:10Antibody Structure
65.4K
Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
65.4K
02:22Structures of Solids
17.6K
Solids in which the atoms, ions, or molecules are arranged in a definite repeating pattern are known as crystalline solids. Metals and ionic compounds typically form ordered, crystalline solids. A crystalline solid has a precise melting temperature because each atom or molecule of the same type is held in place with the same forces or energy. Amorphous solids or non-crystalline solids (or, sometimes, glasses) which lack an ordered internal structure and are randomly arranged. Substances that...
17.6K