Martin Humphries
LAB

Integrins as molecules



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.


Bent integrin conformation

Bent integrin conformation

PDB entry 3FCS

 
Extended integrin conformation

Extended integrin conformation

PDB entry 3FCU


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.


Integrin conformational change

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?


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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