Does the Integrin αA Domain Act as a Ligand for its βA Domain?

Alonso, José L.; Essafi, Makram; Xiong, Jian; Stehle, Thilo; Arnaout, M. Amin

doi:10.1016/s0960-9822(02)00852-7

Cited by 99 publications

(105 citation statements)

References 21 publications

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“…Glu-310 in ␣ L , is indispensable for Mn 2ϩ -induced activation of ␤ 2 integrins (32,33,44). Mutation of either the metal-coordinating MIDAS residue Ser-114 in the ␤ 2 I domain or Glu-310 in the ␣ L I domain C-terminal linker totally abolished Mn 2ϩ -induced ICAM-1 binding (Fig.…”

Section: The Activating Effect Of Compound 4 Is Inhibited By Compoundmentioning

confidence: 87%

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A Small Molecule Agonist of an Integrin, αLβ2

Yang

Carman

Kim

et al. 2006

Journal of Biological Chemistry

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Integrins are a large family of ␣/␤ heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion and transduce signals bidirectionally across the plasma membrane. Integrin ␣ L ␤ 2 (lymphocyte function associated antigen-1 (LFA-1)) 5 belongs to the ␤ 2 integrin subfamily and is constitutively expressed on all leukocytes. ␣ L ␤ 2 remains in a low affinity state in resting lymphocytes and undergoes dramatic conformational change during lymphocyte activation, which greatly increases its binding affinity for its ligands intercellular adhesion molecule -1, -2, and -3 (ICAM-1, -2, and -3). Regulation of ␣ L ␤ 2 activation is pivotal for controlling leukocyte trafficking and immune responses in health and diseases (1-3).␣ L ␤ 2 is an important pharmaceutical target for treating autoimmune and inflammatory diseases (4 -8). A humanized antibody to ␣ L ␤ 2 that blocks its binding to the ligand ICAM-1 has been approved by the FDA for treatment of psoriasis, a T cellmediated autoimmune disease of the skin (9, 10). Furthermore, small molecule antagonists of ␣ L ␤ 2 have been discovered and are in development (11)(12)(13)(14)(15)(16)(17).␣ L ␤ 2 contains two von Willebrand factor-type A domains, the inserted (I) domains in the ␣ L and the ␤ 2 subunits (18 -20). Both ␣ L I and ␤ 2 I domains have a Rossman fold (i.e. a central ␤-sheet surrounded by ␣-helices) with a metal ion-dependent adhesion site (MIDAS) formed by ␤-␣ loops at the "top" face of the domain (20 -23). In ligand binding the Mg 2ϩ ion in the MIDAS of the ␣ L I domain coordinates directly to a Glu residue that is in the center of the ligand binding sites in domain 1 of 24). The affinity of the ␣ L I domain for ICAMs is regulated by downward axial displacement of its C-terminal ␣7 helix, which is conformationally linked to reshaping of MIDAS loops and increases affinity for ligand by up to 10,000-fold (25, 26). During activation, the ␤ I domain undergoes similar ␣7 helix downward axial movement, which is induced by the swing out of the hybrid domain (27)(28)(29)(30). 6 Previous data suggested that when activated, the ␤ 2 I domain binds (through the Mg 2ϩ in its MIDAS) to the Glu residue (Glu-310) in the C-terminal linker of the ␣ L I domain, exerts a downward pull on its ␣7 helix, and thereby activates the ␣ L I domain (Fig. 1A) (32, 33).Two distinct classes of small molecule antagonists of ␣ L ␤ 2 have been developed as anti-inflammatory agents. One group of antagonists binds the hydrophobic pocket underneath the ␣7 helix of the ␣ L I domain (e.g. LFA703 or BIRT377), blocks the downward axial movement of the ␣7 helix, and inhibits ligand binding of ␣ L ␤ 2 allosterically by stabilizing the ␣ L I domain in the low affinity conformation (11)(12)(13)(14)34). These antagonists are called ␣ I allosteric inhibitors. The other group of antagonists appears to bind to the ␤ 2 I domain MIDAS near a key regulatory interface with the ␣ L I domain, blocking communication of conformational change to the ␣ L I domain while at the same time ac...

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Section: The Activating Effect Of Compound 4 Is Inhibited By Compoundmentioning

confidence: 87%

“…6 Previous data suggested that when activated, the ␤ 2 I domain binds (through the Mg 2ϩ in its MIDAS) to the Glu residue (Glu-310) in the C-terminal linker of the ␣ L I domain, exerts a downward pull on its ␣7 helix, and thereby activates the ␣ L I domain (Fig. 1A) (32,33).…”

mentioning

confidence: 99%

A Small Molecule Agonist of an Integrin, αLβ2

Yang

Carman

Kim

et al. 2006

Journal of Biological Chemistry

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“…Altogether, our model would expect that 1) the ␣ M I-domain plays a major role in C3bi binding to the intact receptor; 2) among the three individual domains that form the composite C3bi-binding site, the ␤-propeller and the ␤ 2 I-domain reside relatively close to each other in space, whereas the ␣ M I-domain is located farther apart; and 3) high affinity ligand binding to ␣ M ␤ 2 requires optimal orientations among all three ligand binding domains, and therefore spatial changes relative to each other could affect ligand binding and thereby provide a potential means to control the affinity state of the integrin receptor ("inside-out" signaling). Two other models have been proposed in the literature, in which the MIDAS motif of the ␣ M I-domain was shown to project away from the W4 blade of the ␤-propeller and the ␤ 2 I-domain (36,37). Further studies will be needed to test the validities of these different models.…”

Section: C3bi-binding Site Within the ␣ M ␤-Propellermentioning

confidence: 99%

The Fourth Blade within the β-Propeller Is Involved Specifically in C3bi Recognition by Integrin αMβ2

Zhang

2003

Journal of Biological Chemistry

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“…Allosteric changes initiated from inside or outside the cell are propagated along the integrin 'stalk' to modulate affinity and to link ligand binding with intracellular signaling pathways. I domains in the § and g subunits are in close apposition in the integrin holoreceptor and it has been proposed that interaction between the two domains serves to modulate the conformation of the ligand-binding site in the § I domain [18]. One particularly helpful approach has been to bypass allosteric regulation of the § I domain by introducing mutations.…”

Section: Introductionmentioning

confidence: 99%

Role of the αI domain in ligand binding by integrin αEβ7

et al. 2003

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The I domain of integrin § E was modeled on the crystal structure of that in CD11b and mutated to produce an open (high affinity) or closed (low affinity) conformation. K562 transfectants expressing mutant § E and wild-type g 7 were tested for adhesion to E-cadherin-Fc. Downward displacement of the C terminus of the § I domain with a disulfide bridge enhanced adhesion and Mn 2+ dependency. Adhesion greatly exceeded that observed using wild type integrin under similar conditions. The closed integrin gave poor adhesion which was greatly improved by PMA-induced clustering. Blocking g 7 function with a g I domain-specific antibody inhibited the wild-type but not the locked open integrin. Isolated open § I domain expressed on K562 cells showed strong Mn 2+ -dependent adhesion to E-cadherin, whereas the wild-type version was ineffective. § E g 7 was shown to bind to monomeric E-cadherin but to only one component of dimeric E-cadherin. Finally, we report that M290, a functionblocking antibody, bound to a conformation-sensitive epitope near the rim of the § I domain MIDAS and recognized wild-type and closed § I domain but not the open conformation. The results broadly support the paradigm for affinity regulation by conformational change that has been established for g 2 integrins. Nevertheless, for § E, the fully open conformation may represent an extreme situation that does not occur physiologically.

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Does the Integrin αA Domain Act as a Ligand for its βA Domain?

Cited by 99 publications

References 21 publications

A Small Molecule Agonist of an Integrin, αLβ2

A Small Molecule Agonist of an Integrin, αLβ2

The Fourth Blade within the β-Propeller Is Involved Specifically in C3bi Recognition by Integrin αMβ2

Role of the αI domain in ligand binding by integrin αEβ7

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