propagate via the activation of specific signaling pathways [7]. In a
simple context, the mechanical load can accelerate the association
or dissociation of protein–ligand bonds [8]. In the case of adhesion
proteins, that exhibit catch-bond behavior, mechanical loads can
produce changes in the conformation of the proteins that lead to
high affinity for a binding partner [9–11].
Deciphering how fundamental physical principles are controlled by protein interactions is central to understand how forces
are converted into biochemical signals. Elucidation of the specificity, selectivity, and regulatory mechanisms involved in protein–protein interactions can therefore provide important insights into
many biological processes such as cell proliferation, cell migration,
and cell polarity. Structural studies have revealed that mechanosensitive proteins with multiple domains and flexible interdomain
interfaces can pass through multiple conformations [12, 13]. For
example, a bent conformation can open up to a straighter arrangement of domains along the direction of the applied force. These
changes in conformation result in modification of the affinity for
the binding partners, exposure or hiding of different catalytic
domains that will trigger differential intracellular signaling
responses or even redistribution of the protein within the cell
[14–16]. Among the proteins that mediate protein–protein interactions, there is the large PDZ (postsynaptic density 95/Disc
large/Zonula occludens) family. Most of the PDZ proteins are
multimodular scaffold proteins and often contain multiple PDZ
domains which can interact with various binding partners and
thereby assemble supramolecular signaling complexes [17].
As PDZ domains interact with motifs present in many proteins,
understanding the regulatory mechanism of PDZ mediated interactions is important to gain insight into biological processes. So far,
posttranslational modifications, autoinhibition, and allosteric interactions have been proposed to regulate PDZ-mediated interactions
and thus intracellular signaling [18], but little is known about the
impact of mechanical inputs on PDZ proteins. In this review, we
will focus on the current knowledge on the mechanoregulation of
PDZ proteins, focusing on few recent findings.
2 PDZ Proteins as Mechanotransducers
Biological mechanotransducers can be defined as a single protein or
a protein complex that produce or enable a chemical signal in
response to mechanical stimuli. These mechanotransducers can
participate in mechanoreception and mechanotransmission as
direct mechanosensitive structure, which respond by altering their
conformation upon force loads, or as second line mechanotransducers. Among the mechanotransducer proteins studied so far, the
PDZ protein family is emerging as a new pool of protein sensitive to
258
Elsa Bazellie ` res and Andre ´ Le Bivic
simple context, the mechanical load can accelerate the association
or dissociation of protein–ligand bonds [8]. In the case of adhesion
proteins, that exhibit catch-bond behavior, mechanical loads can
produce changes in the conformation of the proteins that lead to
high affinity for a binding partner [9–11].
Deciphering how fundamental physical principles are controlled by protein interactions is central to understand how forces
are converted into biochemical signals. Elucidation of the specificity, selectivity, and regulatory mechanisms involved in protein–protein interactions can therefore provide important insights into
many biological processes such as cell proliferation, cell migration,
and cell polarity. Structural studies have revealed that mechanosensitive proteins with multiple domains and flexible interdomain
interfaces can pass through multiple conformations [12, 13]. For
example, a bent conformation can open up to a straighter arrangement of domains along the direction of the applied force. These
changes in conformation result in modification of the affinity for
the binding partners, exposure or hiding of different catalytic
domains that will trigger differential intracellular signaling
responses or even redistribution of the protein within the cell
[14–16]. Among the proteins that mediate protein–protein interactions, there is the large PDZ (postsynaptic density 95/Disc
large/Zonula occludens) family. Most of the PDZ proteins are
multimodular scaffold proteins and often contain multiple PDZ
domains which can interact with various binding partners and
thereby assemble supramolecular signaling complexes [17].
As PDZ domains interact with motifs present in many proteins,
understanding the regulatory mechanism of PDZ mediated interactions is important to gain insight into biological processes. So far,
posttranslational modifications, autoinhibition, and allosteric interactions have been proposed to regulate PDZ-mediated interactions
and thus intracellular signaling [18], but little is known about the
impact of mechanical inputs on PDZ proteins. In this review, we
will focus on the current knowledge on the mechanoregulation of
PDZ proteins, focusing on few recent findings.
2 PDZ Proteins as Mechanotransducers
Biological mechanotransducers can be defined as a single protein or
a protein complex that produce or enable a chemical signal in
response to mechanical stimuli. These mechanotransducers can
participate in mechanoreception and mechanotransmission as
direct mechanosensitive structure, which respond by altering their
conformation upon force loads, or as second line mechanotransducers. Among the mechanotransducer proteins studied so far, the
PDZ protein family is emerging as a new pool of protein sensitive to
258
Elsa Bazellie ` res and Andre ´ Le Bivic