Related Experiment Video
Updated: Feb 7, 2026
10:08
Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
Published on: August 28, 2012
12.3K
Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation
Ashley Z Guo1, Aaron M Fluitt1, Juan J de Pablo1
1Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, USA.
The Journal of Chemical Physics
|July 16, 2018
Summary
Early aggregation of human islet amyloid polypeptide (hIAPP) into dimers is crucial for type II diabetes. Simulations reveal a key intermediate with transient beta-sheet structure, guiding therapeutic development.
Area of Science:
- Biochemistry
- Computational Biology
- Diabetes Research
Background:
- Human islet amyloid polypeptide (hIAPP) aggregation is linked to type II diabetes.
- Early-stage prefibrillar hIAPP species are proposed to be cytotoxic.
Purpose of the Study:
- To investigate the early-stage dimerization of hIAPP in water.
- To identify key intermediates and free energy barriers in hIAPP dimer formation.
Main Methods:
- Atomistic molecular dynamics simulations.
- Enhanced sampling techniques: bias-exchange metadynamics and finite temperature string method.
Main Results:
- Identified pathways and free energy barriers for hIAPP dimer formation.
- Revealed relative conformational stabilities of the hIAPP dimer.
- Characterized an intermediate with transient beta-sheet structure.
Conclusions:
- The initial dimerization of hIAPP involves overcoming a significant free energy barrier.
- An intermediate with transient beta-sheet character precedes the formation of an entropically stabilized dimer.
- Understanding these early aggregation steps is vital for developing type II diabetes therapeutics.
Related Concept Videos
03:03Amyloid Fibrils
12.0K
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,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
12.0K
03:03Amyloid Fibrils
6.5K
6.5K
01:31Mechanism of Lamellipodia Formation
3.7K
Cells migrating in response to external stimuli form lamellipodia, which are thin membrane protrusions supported by a mesh of linked, branched, or unbranched actin filaments. These actin filaments interact with myosin motor proteins, creating the dynamic actomyosin complex within the cytoskeleton. Contractility, or the ability to generate contractile stress, is inherent to the actomyosin complex. It helps cells detect the stiffness of the surrounding ECM and exert contractile force for...
3.7K
01:39Mechanism of Filopodia Formation
3.2K
Filopodia are thin, actin-rich cellular protrusions that play an important role in many fundamental cellular functions. They vary in their occurrence, length, and positioning in different cell types, suggesting their diverse roles.
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication...
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication...
3.2K
00:59Mechanisms of Membrane Domain Formation
3.9K
Different physical properties of lipids and proteins allow them to localize and form distinct islands or domains in the membrane. Some membrane domains are formed due to protein-protein interactions, whereas others are formed due to the presence of specific lipids such as sphingolipids and sterols—for example, large proteins, such as bacteriorhodopsin, aggregate and create distinct domains.
Another mechanism for membrane domain formation involves membrane proteins interacting with...
Another mechanism for membrane domain formation involves membrane proteins interacting with...
3.9K
01:14Aldehydes and Ketones with Amines: Enamine Formation Mechanism
7.7K
Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to...
7.7K