Integrin Structure, Allostery, and Bidirectional Signaling

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What are integrins?

Integrins are receptors that are heterodimeric, cell surface glycoproteins. They are composed of two subunits, the alpha and beta subunits forming a dimer.

Twenty-four integrins have been identified so far and this diversity in integrins is a result of the different pairings of eighteen alpha- and eight beta subunits. An additional point - each of the subunits have multiple additional domains.

Nine of the eighteen mammalian alpha subunits contain an additional vWFA domain. This is also known as an A or the I domain. Nine of the aforementioned integrins belong to the alpha A-containing subclass.

The N-terminal of each of these two subunits forms a ligand binding globular head, connected to the membrane by a long (approximately one hundred seventy angstrom) stalk.

Ligand binding to integrin requires divalent cations and involves solvent exposed aspartate or a glutamate in the alpha A-containing subclass.

Integrins recognize a large number of physiologic ligands - including soluble and surface bound proteins.

Integrin binding results in force generation at focal contacts which is the site where integrins and ligands bind which affects contractile apparatus of the cell and influences assembly and remodeling of extracellular matrix.

Integrin family slide two

There is diversity in integrin binding as well. High affinity binding to ligands needs a conformational switch. The switch to high affinity state is rapid (less than one second) and reversible in less than a minute.

Here is a brief overview of how integrin binding and signal transmission occurs -

Alpha subunit intro slide -

The Closed Conformation slide -

The open conformation slide -

Structure of the ectodomain slide -

Formation of the heterodimer slide -

The Extracellular Head Interface

Transmembrane and Cytoplasmic Interaction

The three cation sites of BA slide -

Difference between MIDAS, ADMIDAS and LIMBS -

Two. ADMIDAS (Adjacent to MIDAS)

Three. LIMBS Ligand-Associated Metal-Binding Site

Integrin ligand binding site slide -

Ligand binding and conformational change slide - A review of the steps that took place -

Cytoplasmic tail slide -

Transmembrane segments slide -

Ectodomain - TM connection slide -

Shift from Parallel to Tilted Orientation

Functional Implications

Inside Out versus Outside In signalling slide -

The Deadbolt Model slide -

Then how is the high affinity state achieved?

Overview

The document provides a comprehensive overview of integrin structure, highlighting the allosteric regulation of their activity and the bidirectional signaling mechanisms that affect cell adhesion and extracellular matrix interactions. It emphasizes the significance of conformational changes in integrins that allow them to switch between high and low affinity states for ligands.

Key Points

1Integrins are heterodimeric glycoproteins critical for cell adhesion and signaling
2The transition between high and low affinity states is essential for integrin function
3Integrin binding requires divalent cations and involves conformational changes
4Inside-out and outside-in signaling pathways mediate integrin functions
5The ectodomain structure is essential for ligand interaction and cellular responses

Details

Category: Biology and Natural Sciences

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