Related Experiment Video
Updated: Nov 18, 2025
09:14
Static Adhesion Assay for the Study of Integrin Activation in T Lymphocytes
Published on: June 13, 2014
16.5K
Insight Into Pathological Integrin αIIbβ3 Activation From Safeguarding The Inactive State
Alan J Situ1, Jiyoon Kim2, Woojin An3
1Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Journal of Molecular Biology
|February 4, 2021
Summary
A newly discovered structural motif safeguards the integrin αIIbβ3 receptor by destabilizing its inactive state. This mechanism identifies hydrodynamic forces as a pathological stimulus, preventing fatal thrombosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Integrin αIIbβ3 is crucial for platelet aggregation and thrombosis.
- Existing inhibitors targeting physiological activation pathways may not fully prevent thrombosis.
- An unidentified activation pathway for integrin αIIbβ3 is suspected.
Purpose of the Study:
- To discover and characterize a novel structural motif safeguarding integrin αIIbβ3.
- To identify the pathological activation stimulus for integrin αIIbβ3.
- To understand the evolutionary advantage of this safeguard.
Main Methods:
- Structural analysis of the integrin αIIbβ3 receptor at the extracellular membrane border.
- Investigating the destabilization energy of the inactive state.
- Assessing the impact of hydrodynamic forces versus physiological agonists on receptor activation.
Main Results:
- Discovery of an overpacked αIIb(W968)-β3(I693) contact destabilizing the inactive integrin αIIbβ3 state by ~1.0 kcal/mol.
- Hydrodynamic forces, but not physiological agonists, mitigate this destabilization, acting as a pathological stimulus.
- The safeguard is triggered solely by pathological stimuli, increasing the energy barrier between inactive and active states.
Conclusions:
- Integrin αIIbβ3 possesses an evolved safeguard against pathological activation.
- Hydrodynamic forces represent a mechanical activation pathway for integrin αIIbβ3.
- This mechanism prevents fatal thrombosis without increasing bleeding risk.
More Related Videos
Related Concept Videos
01:15Activation of Integrins
4.5K
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
4.5K
01:17Intracellular Signaling Affects Focal Adhesions
3.2K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
3.2K
01:10Integrins
4.8K
Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
4.8K
01:20The JAK-STAT Signaling Pathway
10.3K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
10.3K
01:22Amplifying Signals via Enzymatic Cascade
15.3K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
15.3K
01:30Assembly of Signaling Complexes
6.2K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.2K