Introduction to Integrin Activation[Edit]
Integrin activation is an important mechanism through which cells regulate integrin function by manipulating the ligand affinity of integrins spatially and temporally. Structural and functional studies suggest that integrins can exist in different ligand affinity states – low, intermediate and high (reviewed in [1]). Crystal structures have revealed that integrin heterodimers, occur in an inactive, bent V-shape with the head close to the membrane-proximal regions of the legs [2, 3], maintained by the α/β salt bridge at the inner membrane region and helix packing of the transmembrane (TM) region [4]. This low affinity structure undergoes rapid, reversible conformational changes to increase ligand affinity, termed “activation” (reviewed in [5, 6, 7]).
The Structural hallmarks of integrin activation are:
a) complete extension of the extracellular domains and
b) separation of the cytoplasmic leg domains (structural rearrangements detailed in [8, 9]).
This process facilitates integrin-mediated signaling, thus mechano-sensing and -transmitting.
Integrin can be activated from two directions, from the inside by the regulated binding of proteins to the cytoplasmic tails, and from the outside by multivalent ligand binding. In either case, talin binding to the integrin β tails is an essential and the final common step ([10], reviewed in [11]). Though the two processes are conceptually separate, they are mutually cooperative i.e one can lead to the other. Some structural studies done with force application to mimic ligand/intracellular protein suggested that the combined action of these two events favor the transition from the closed, low affinity to a open, high affinity conformation of integrin [12]. Activation leads to bidirectional signaling crucial in a variety of anchorage-dependent events such as adhesion, cell spreading, migration, polarity and organization of the ECM leading to physiological changes (reviewed in [13]).
Here we discuss only well-established events that occur at the close proximity of integrin molecules localized on the plasma membrane.
a) complete extension of the extracellular domains and
b) separation of the cytoplasmic leg domains (structural rearrangements detailed in [8, 9]).
This process facilitates integrin-mediated signaling, thus mechano-sensing and -transmitting.
Integrin can be activated from two directions, from the inside by the regulated binding of proteins to the cytoplasmic tails, and from the outside by multivalent ligand binding. In either case, talin binding to the integrin β tails is an essential and the final common step ([10], reviewed in [11]). Though the two processes are conceptually separate, they are mutually cooperative i.e one can lead to the other. Some structural studies done with force application to mimic ligand/intracellular protein suggested that the combined action of these two events favor the transition from the closed, low affinity to a open, high affinity conformation of integrin [12]. Activation leads to bidirectional signaling crucial in a variety of anchorage-dependent events such as adhesion, cell spreading, migration, polarity and organization of the ECM leading to physiological changes (reviewed in [13]).
Here we discuss only well-established events that occur at the close proximity of integrin molecules localized on the plasma membrane.