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Structural basis of blocking integrin activation and deactivation for anti-inflammation.

Park EJ, Yuki Y, Kiyono H, Shimaoka M - J. Biomed. Sci. (2015)

Bottom Line: Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders.While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration.Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie, 514-8507, Japan. epark@doc.medic.mie-u.ac.jp.

ABSTRACT
Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders. Integrin activation triggered by inflammatory mediators or signaling pathway is a key step to initiate leukocyte migration to inflamed tissues; however, an appropriately regulated integrin deactivation is indispensable for maintaining productive leukocyte migration. While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration. Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

No MeSH data available.


Related in: MedlinePlus

Structural components to stabilize inactive integrin conformation. a The cytoplasmic salt bridge is formed between the arginine residue in the α subunit and the glutamate residue in the β subunit, thereby clasping the α/β integrin cytoplasmic tails. A mutation to disrupt the salt bridge results in promoting the cytoplasmic dissociation, thereby inducing integrin activation. b A conserved isoleucine at the α I domain C-terminal helix acts as a ratchet to stabilize the inactive conformation. A downward shift of the C-terminal helix is mediated by an interdomain interaction by the β I domain (also known as I-like domain). c Ca2+ binding site ADMIDAS in the β I domain favors the inactive low-affinity integrin headpiece conformation. A mutation to disrupt the Ca2+ binding site induces the constitutively active conformation by facilitating the conformational swing out of the hybrid domain
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Fig3: Structural components to stabilize inactive integrin conformation. a The cytoplasmic salt bridge is formed between the arginine residue in the α subunit and the glutamate residue in the β subunit, thereby clasping the α/β integrin cytoplasmic tails. A mutation to disrupt the salt bridge results in promoting the cytoplasmic dissociation, thereby inducing integrin activation. b A conserved isoleucine at the α I domain C-terminal helix acts as a ratchet to stabilize the inactive conformation. A downward shift of the C-terminal helix is mediated by an interdomain interaction by the β I domain (also known as I-like domain). c Ca2+ binding site ADMIDAS in the β I domain favors the inactive low-affinity integrin headpiece conformation. A mutation to disrupt the Ca2+ binding site induces the constitutively active conformation by facilitating the conformational swing out of the hybrid domain

Mentions: Integrin molecules contain the intrinsic structural components that favor the default bent conformations, thereby preventing spontaneous aberrant integrin activation in the absence of proper stimulatory signals. The cytoplasmic GFFKR motif constitutes an important intrinsic component that facilitates integrin deactivation, thereby favoring a default inactive conformation. Deletion of the GFFKR motif or mutation of the arginine to alanine are designed to disrupt the cytoplasmic salt bridge, and have been shown to make constitutively active integrins as a result of impaired deactivation (Fig. 3a).Fig. 3


Structural basis of blocking integrin activation and deactivation for anti-inflammation.

Park EJ, Yuki Y, Kiyono H, Shimaoka M - J. Biomed. Sci. (2015)

Structural components to stabilize inactive integrin conformation. a The cytoplasmic salt bridge is formed between the arginine residue in the α subunit and the glutamate residue in the β subunit, thereby clasping the α/β integrin cytoplasmic tails. A mutation to disrupt the salt bridge results in promoting the cytoplasmic dissociation, thereby inducing integrin activation. b A conserved isoleucine at the α I domain C-terminal helix acts as a ratchet to stabilize the inactive conformation. A downward shift of the C-terminal helix is mediated by an interdomain interaction by the β I domain (also known as I-like domain). c Ca2+ binding site ADMIDAS in the β I domain favors the inactive low-affinity integrin headpiece conformation. A mutation to disrupt the Ca2+ binding site induces the constitutively active conformation by facilitating the conformational swing out of the hybrid domain
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4495637&req=5

Fig3: Structural components to stabilize inactive integrin conformation. a The cytoplasmic salt bridge is formed between the arginine residue in the α subunit and the glutamate residue in the β subunit, thereby clasping the α/β integrin cytoplasmic tails. A mutation to disrupt the salt bridge results in promoting the cytoplasmic dissociation, thereby inducing integrin activation. b A conserved isoleucine at the α I domain C-terminal helix acts as a ratchet to stabilize the inactive conformation. A downward shift of the C-terminal helix is mediated by an interdomain interaction by the β I domain (also known as I-like domain). c Ca2+ binding site ADMIDAS in the β I domain favors the inactive low-affinity integrin headpiece conformation. A mutation to disrupt the Ca2+ binding site induces the constitutively active conformation by facilitating the conformational swing out of the hybrid domain
Mentions: Integrin molecules contain the intrinsic structural components that favor the default bent conformations, thereby preventing spontaneous aberrant integrin activation in the absence of proper stimulatory signals. The cytoplasmic GFFKR motif constitutes an important intrinsic component that facilitates integrin deactivation, thereby favoring a default inactive conformation. Deletion of the GFFKR motif or mutation of the arginine to alanine are designed to disrupt the cytoplasmic salt bridge, and have been shown to make constitutively active integrins as a result of impaired deactivation (Fig. 3a).Fig. 3

Bottom Line: Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders.While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration.Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie, 514-8507, Japan. epark@doc.medic.mie-u.ac.jp.

ABSTRACT
Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders. Integrin activation triggered by inflammatory mediators or signaling pathway is a key step to initiate leukocyte migration to inflamed tissues; however, an appropriately regulated integrin deactivation is indispensable for maintaining productive leukocyte migration. While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration. Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

No MeSH data available.


Related in: MedlinePlus