Morphology and domain structure
Morphologically, an integrin is divided into a "head", "legs", and transmembrane and cytoplasmic regions.
- The "head" faces the extracellular space and has a globular structure. It is responsible for ligand binding. In the α-chain, the head region is represented by a β-propeller domain.
- The "legs" are formed by epidermal growth factor-like domains and adjoin the cell membrane.
- The cytoplasmic region is usually short and interacts with the cytoskeletal protein talin.
About half of all known α-chains have an additional αI domain (von Willebrand factor domain) that attaches to the β-propeller. In such molecules, it is the αI-chain that binds the ligand. If this domain is absent, the head region of the β-chain acts as the main binding link.
Activation and conformational changes
In a resting cell (e.g., a circulating leukocyte), integrins are inactive. Their binding capacity is minimal, and the molecule itself is in a bent state: the "legs" are folded, and the "head" is pressed against the membrane.
Activation is triggered by chemokines and proceeds in two stages:
- Extension. The "legs" straighten out, the molecule transitions to an extended configuration, but the active site is still closed.
- Opening. The α- and β-chains (regions of the "legs") separate. The active site opens for the ligand.
The key element of the active site is MIDAS (Metal ion-dependent adhesion site). Under physiological conditions, it holds a Mg²⁺ ion. Upon activation, the receptor's affinity for the ligand increases by several orders of magnitude, ensuring reliable cell adhesion. The process is reversible: when intracellular cAMP levels rise, the integrin is inactivated again.
Signal transduction ("outside-in")
Although integrins tightly bind the cell to the matrix or endothelium, they lack intrinsic enzymatic or signaling motifs in their cytoplasmic portion.
A cascade is used to transmit the activation signal inside the cell:
- The activated receptor clusters and contacts other membrane molecules containing an ITAM motif.
- Tyrosine kinases of the Src family associate with the cytoplasmic tail of integrin.
- Src kinases phosphorylate the ITAM motif.
- The phosphorylated ITAM activates Syk-family kinases, which trigger a cellular response (degranulation, oxidative burst, actin cytoskeleton reorganization).
Major integrin families
In immunology, the most important receptors are those whose nodal chains are β1, β2, and β7 (these are the ones capable of combining with many different α-chains).
| Family | Alternative name | Expression features and ligands |
|---|---|---|
| β1 | VLA molecules | Widely represented on leukocytes. They bind to collagen, laminin, fibronectin, and the VCAM-1 molecule. |
| β2 | LeuCAM | Present exclusively on leukocytes. Key representatives: LFA-1 and Mac-1. The main receptors for them are ICAM group molecules. |
| β7 | - | Localized mainly on T lymphocytes. Integrin α4β7 is the main receptor for cell migration into the intestinal mucosa (recognizes MadCAM). |
To avoid confusing ligands, remember: β2-integrins (LeuCAM) predominantly work with the ICAM family, while β1-integrins (VLA) work with VCAM-1 and the extracellular matrix.
Class and exam questions
Which ions are necessary for ligand binding to an integrin?
The process critically depends on divalent ions, primarily magnesium ions (Mg²⁺), which are fixed in the MIDAS active site. The molecule also contains "pockets" for calcium (Ca²⁺).
What is LFA-1 and to which family does it belong?
LFA-1 (αLβ2, or CD11a/CD18) is the main lymphocyte integrin belonging to the β2-integrin family. It binds to all molecules of the ICAM family.
Is the presence of the RGD sequence mandatory for integrin function?
No. Although receptors recognize the RGD sequence in matrix or complement components, integrin binding to crucial cellular molecules ICAM and VCAM does not depend on it.
What else to study on this topic
- Functional features of LFA-1, Mac-1, and p150/p95 molecules
- Structure and induction of intercellular adhesion molecules (ICAM, VCAM-1)
- PeCAM molecule (CD31) and mechanisms of homotypic interaction
- The unique addressin MadCAM and mechanisms of intestinal lymphocyte homing
- Role of chemoattractants and fMLP in directed leukocyte migration
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