Integrins as molecules

Integrins as molecules

Integrins are cell-surface adhesion receptors. They have large extracellular domains, single-pass transmembrane regions and short cytoplasmic domains. The extracellular “heads” of integrins bind to proteins of the extracellular matrix or to counter-receptors on other cells; the cytoplasmic “tails” are able to link to the actin cytoskeleton. Integrins are able to transduce signals in both directions across the cell membrane, thus integrating the intracellular and extracellular environments. This provides a means for cells to sense their environment and to modulate and co-ordinate essential aspects of cell behaviour crucial to the development and maintenance of organisms.

Bent integrin conformation

Bent integrin conformation

PDB entry 3FCS

Extended integrin conformation

Extended integrin conformation

PDB entry 3FCU

General introduction

Integrins as molecules – general intro

Integrins as molecules: the Velcro of our body

Written by Janet Askari

Integrins are sticky molecules that are found on the surface of all cells. One of their functions is to hold our body together and they do this by acting as a type of molecular “Velcro” that keeps our organs and tissues from falling apart.

Integrins also act as transmitters and receivers of information between the outside and inside of cells. This enables them to respond appropriately to changes in the cell’s environment. In this way, integrins receive signals from the cell’s surroundings and in turn transmit the information into the cell. These signals tell the cell, for example, to divide to help repair a wound or to move to a site of infection to fight a disease.

The control of these signals requires very fine tuning. This is regulated by shape changes in the integrin molecules. In simple terms, one shape corresponds to an integrin that is switched off and another shape to an integrin that is switched on. Research is being performed to understand exactly how these shapes changes happen, how they are translated into signals and how the signals tell a cell what to do in response.

Sometimes signalling by integrins goes wrong, which can lead to disease. When integrins malfunction, cells start to move and stick in the wrong place. These mistakes can result in conditions like blocked arteries and heart disease, secondary cancerous tumours and certain autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease. A detailed understanding of how integrin signalling works can potentially lead to the manufacture of new medicines to treat these life-threatening disorders.

General introduction

Integrins as molecules – general intro

Integrins as molecules: the Velcro of our body

Written by Janet Askari

Integrins are sticky molecules that are found on the surface of all cells. One of their functions is to hold our body together and they do this by acting as a type of molecular “Velcro” that keeps our organs and tissues from falling apart.

Integrins also act as transmitters and receivers of information between the outside and inside of cells. This enables them to respond appropriately to changes in the cell’s environment. In this way, integrins receive signals from the cell’s surroundings and in turn transmit the information into the cell. These signals tell the cell, for example, to divide to help repair a wound or to move to a site of infection to fight a disease.

The control of these signals requires very fine tuning. This is regulated by shape changes in the integrin molecules. In simple terms, one shape corresponds to an integrin that is switched off and another shape to an integrin that is switched on. Research is being performed to understand exactly how these shapes changes happen, how they are translated into signals and how the signals tell a cell what to do in response.

Sometimes signalling by integrins goes wrong, which can lead to disease. When integrins malfunction, cells start to move and stick in the wrong place. These mistakes can result in conditions like blocked arteries and heart disease, secondary cancerous tumours and certain autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease. A detailed understanding of how integrin signalling works can potentially lead to the manufacture of new medicines to treat these life-threatening disorders.

Scientific details

Integrins as molecules – scientific detail

Integrins are cell-surface receptors with large extracellular domains, single-pass transmembrane regions and short cytoplasmic tails. In mammals, 18 α subunits pair with 8 β subunits to produce a total of 24 integrin molecules. These α,β heterodimers bind to proteins of the extracellular matrix or to counter-receptors of the immunoglobulin superfamily on other cells. The cytoplasmic tails of integrins are able to link to the actin cytoskeleton and so provide a means for the cell to sense and respond to its environment. Integrins are able to transduce signals in both directions across the cell membrane, integrating the intracellular and extracellular environment, which enables them to modulate and co-ordinate essential aspects of cell behaviour crucial to the development and maintenance of organisms.

The overall structure of an integrin can be likened to a head on two legs. The headpiece forms the ligand-binding pocket and the legs, which have a flexible knee or “genu”, extend down to the cytoplasmic tails. To enable integrins to perform their diverse functions, their activity must be precisely controlled, and this is achieved by dynamic conformational changes that regulate their activation state. At present, three conformational states have been identified: (1) inactive with low affinity for ligand, (2) “primed” or active with high affinity for ligand and (3) ligand-bound. Currently, the most widely accepted model of integrin activation correlates these states with integrin conformations that are bent at the knee (as seen in crystal structures), extended and extended with an open headpiece, respectively.

Activation or priming of integrins from inside the cell (inside-out signalling) is initiated by the binding of the cytoskeletal protein talin to the β-subunit tail. This causes a destabilisation of the interaction of the cytoplasmic and transmembrane domains of the two integrin subunits, which leads to an unbending of the ligand-binding headpiece to an upright position together with other conformational changes that prime the integrin to bind ligand. Once ligand has bound, the open-headpiece conformation is stabilised, which instigates a separation of the subunit legs. This in turn allows recruitment of intracellular signalling molecules to the integrin cytoplasmic tails and initiation of appropriate signalling pathways (outside-in signalling).

Questions that still need to be addressed include the following:

  • Are the shape changes transduced by inside-out and outside-in signalling the same?
  • Do different ligands induce separate shape changes in their specific integrin receptor and, if so, how are these translated into differential signalling pathways?
  • Do intermediate conformations exist and what are the exact structural mechanisms that couple extension and leg separation?
  • What role does physical force play in the modulation of integrin activity?

Further reading

Integrins as molecules – further reading

JA Askari, PA Buckley, AP Mould and MJ Humphries (2009) Linking integrin conformation to function. J. Cell Sci. 122: 165-70. Full text | PubMed entry

AP Mould, SJ Barton, JA Askari, PA McEwan, PA Buckley, SE Craig and MJ Humphries (2003) Conformational changes in the integrin βA-domain provide a mechanism for signal transduction via hybrid domain movement. J. Biol. Chem. 278: 17028-17035. Full text | PubMed entry

AP Mould, JA Askari, S Barton, AD Kline, PA McEwan, SE Craig and MJ Humphries (2002) Integrin activation involves a conformational change in the α1 helix of the β subunit A-domain. J. Biol. Chem. 277: 19800-19805. Full text | PubMed entry

Integrins as molecules – right hand column

Integrin conformational change | Image by Adam Byron

Related galleries

  • Cell-ECM interactions
  • Actin cytoskeleton
  • Microtubule cytoskeleton gallery
  • Integrin proteomics gallery

See: Scientific image galleries