Activation of Platelet αIIbβ3 by an Exogenous Peptide Corresponding to the Transmembrane Domain of αIIb

Yin, Hang; Litvinov, Rustem I.; Vilaire, Gaston; Zhu, Hua; Li, Wei; Caputo, Gregory A.; Moore, David T.; Lear, James D.; Weisel, John W.; DeGrado, William F.; Bennett, Joel S.

doi:10.1074/jbc.m605877200

Cited by 52 publications

(42 citation statements)

References 45 publications

(61 reference statements)

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“…86 Subsequently, homodimerization of ␣IIb TM domain was also reported, and addition of ␣IIb TM domain peptide to platelets induced integrin activation and platelet aggregation. 87,88 Later work also raised the possibility that ␣IIb TMD peptide might activate ␣IIb␤3 by competing with the ␣IIb subunit for ␤3 TMD binding. 89 The earlier works established the concept of disrupting ␣-␤ interaction with a synthetic peptide.…”

Section: Re-creation Of Integrin Activation With Synthetic Peptides Dmentioning

confidence: 99%

Reconstruction of integrin activation

Kim

Ginsberg

2012

Blood

109

108

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IntroductionWhat I cannot create, I do not understand. Richard Feynman Regulation of cell adhesion through cell-matrix or cell-cell interaction is a critical step in various physiologic processes, such as cell migration and anchoring during development of the blood-forming organs, recruitment of cells into sites of inflammation, and aggregation and adhesion of platelets. Integrins are cell surface receptors composed of type I heterodimeric transmembrane proteins, formed by a combination of 18 ␣-subunits and 8 ␤-subunits. Twenty-four integrins have been identified so far. 1 In blood cells, integrins are usually in a resting (inactive) state with low affinity for their ligands; they can quickly switch to an activated, high-affinity state in response to agonists, such as proteases or adenine nucleotides, a process often referred to as inside-out activation or inside-out signaling. [1][2][3][4][5] Disruption of integrin function causes several hematologic diseases. For example, loss of integrin-␣IIb␤3 (GPIIb-IIIa), the most abundant platelet integrin, causes Glanzmann thrombasthenia, a hereditary hemorrhagic disorder. [6][7][8][9] In the early 1990s, investigators also identified Glanzmann thrombasthenia patients whose platelet ␣IIb␤3, although expressed in normal amount, cannot be activated by agonists because of mutations in the ␤3 cytoplasmic domain. 10,11 These mutations, although not fully explained until the recent understanding of talin and kindlin function in integrin regulation, provided important early insight indicating that integrins were regulated from inside-out (reviewed in the last section).Similarly, a subset of integrins, such as ␤2-integrins and ␣4-integrins, are expressed in leukocytes and mediate their adhesion to endothelium during various stages of extravasation during inflammatory responses. Loss of integrin-␤2 (CD18) expression causes leukocyte adhesion deficiency I (LAD I), a disease characterized by recurrent infections. 12 Certain patients with LAD symptoms have normal levels of ␤2-integrins combined with a bleeding diathesis. These patients' leukocytes are defective in ␤2-and ␤1-integrin activation, whereas their platelets also exhibit defects in activation of ␣IIb␤3; this variant is termed LAD III, or Lad1v. [13][14][15][16] The defective integrin activation in these LAD patients is caused by kindlin-3 mutations. [13][14][15]17 Some groups have also suggested the name of integrin activation deficiency disease for these conditions. 14 Furthermore, Kindler syndrome, a skin blistering disease, is the result of defective ␤1-integrin activation caused by kindlin-1 mutations. 18,19 As proteins involved in multiple biologic processes and located at the cell surface, integrins are also readily accessible therapeutic targets. For example, inhibitors of integrin-␣IIb␤3 are currently used in the prevention and treatment of arterial thrombosis in the acute settings of percutaneous coronary intervention. 20 Other integrin-blocking agents against ␣4 are currently used for multiple sclerosis and Croh...

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Section: Re-creation Of Integrin Activation With Synthetic Peptides Dmentioning

confidence: 99%

Reconstruction of integrin activation

Kim

Ginsberg

2012

Blood

109

108

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“…FP experiments were performed as previously described (42,43). Briefly, FP was conducted in an ATF105 spectrofluorometer (Aviv Instrument, Inc) using a 0.3-cm path length cuvette.…”

Section: Sprmentioning

confidence: 99%

Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment

Moore

Nygren

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Binding of the talin-1 FERM (4.1/ezrin/radixin/moesin) domain to the β3 cytosolic tail causes activation of the integrin αIIbβ3. The FERM domain also binds to acidic phospholipids. Although much is known about the interaction of talin-1 with integrins and lipids, the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Here, we examined the thermodynamic interplay between FERM domain binding to phospholipid bilayers and to its binding sites in the β3 tail. We found that although both the F0F1 and F2F3 subdomains of the talin-1 FERM domain bind acidic bilayers, the full-length FERM domain binds with an affinity similar to F2F3, indicating that F0F1 contributes little to the overall interaction. When free in solution, the β3 tail has weak affinity for the FERM domain. However, appending the tail to acidic phospholipids increased its affinity for the FERM domain by three orders of magnitude. Nonetheless, the affinity of the FERM for the appended tail was similar to its affinity for binding to bilayers alone. Thus, talin-1 binding to the β3 tail is a ternary interaction dominated by a favorable surface interaction with phospholipid bilayers and set by lipid composition. Nonetheless, interactions between the FERM domain, the β3 tail, and lipid bilayers are not optimized for a high-affinity synergistic interaction, even at the membrane surface. Instead, the interactions appear to be tuned in such a way that the equilibrium between inactive and active integrin conformations can be readily regulated.cytoskeleton | plasma membrane | platelet aggregation T he integrin αIIbβ3 resides on the platelet surface in equilibrium between resting and active conformations (1-5). On circulating platelets, αIIbβ3 is constrained in its inactive conformation to prevent spontaneous platelet aggregation. Similarly, the cytoskeletal protein talin-1, whose binding to the β3 cytosolic tail (CT) stabilizes the active conformation of αIIbβ3 (6-8), is sequestered away from the β3 CT (9). Besides interacting with integrins, talin-1 interacts with negatively charged phospholipids (10-12) and phosphoinositides (13)(14)(15)(16). Stimuli generated at sites of vascular damage recruit talin-1 to the platelet plasma membrane, thereby promoting αIIbβ3 activation (17-19). Much is known about the interaction of talin-1 with integrins and lipids, but the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Elucidating these interactions is important for understanding events leading to and controlling the formation of integrin complexes and for potential pharmacologic modulation of integrin signaling.Talin-1 is a 250-kD protein containing a 45-kD N-terminal head domain attached via a flexible linker to a 200-kD C-terminal rod domain (7). Because the head domain is packed against the rod domain in its inactive state (20), talin-1 recruitment to the membrane and to integrin β CTs requires disruption of this interaction (1...

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“…Platelets were isolated from the platelet-rich plasma by gel filtration on Sepharose 2B (GE Healthcare, Little Chalfont, United Kingdom) using an elution buffer containing 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , 5.6 mM glucose, 0.35 mg/mL bovine serum albumin, 3.3 mM NaH 2 PO 4 , and 4 mM N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid, pH 7.4, as previously described. 30 Turbidometric measurements of adenosine diphosphate (ADP)-stimulated platelet aggregation were made in a Chrono-Log (Havertown, PA) Lumi Dual-Aggregometer. Platelet suspensions were supplemented with human fibrinogen (Sigma-Aldrich) at final concentrations of 200 g/mL, 1 mM CaCl 2 , and various concentrations of RGDS (Sigma-Aldrich), echistatin, eristostatin, or tirofiban before adding ADP.…”

Section: Measurements Of Platelet Aggregationmentioning

confidence: 99%

Species differences in small molecule binding to αIIbβ3 are the result of sequence differences in 2 loops of the αIIb β propeller

Basani

Zhu

Thornton

et al. 2009

Blood

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Compared with human platelets, rodent platelets are less responsive to peptides and peptidomimetics containing an arginineglycine-aspartic acid (RGD) motif. Using chimeric human-rat ␣IIb␤3 molecules, we found that this difference in Arg-Gly-Asp-Ser (RGDS) sensitivity was the result of amino acid substitutions at residues 157, 159, and 162 in the W3:4-1 loop and an Asp-His replacement at residue 232 in the W4:4-1 loop of the ␣IIb ␤ propeller. Introducing the entire rat W3:4-1 and W4:4-1 loops into human ␣IIb␤3 also decreased the inhibitory effect of the disintegrins, echistatin and eristostatin, and the ␣IIb␤3 antagonists, tirofiban and eptifibatide, on fibrinogen binding, whereas the specific point mutations did not. This suggests that RGDS interacts with ␣IIb in a different manner than with these small molecules. None of these speciesbased substitutions affected the ability of ␣IIb␤3 to interact with RGD-containing macromolecules. Thus, human von Willebrand factor contains an RGD motif and binds equally well to adenosine diphosphatestimulated human and rodent platelets, implying that other motifs are responsible for maintaining ligand binding affinity. Many venoms contain RGD-based toxins. Our data suggest that these species amino acids differences in the ␣IIb ␤-propeller represent an evolutionary response by rodents to maintain hemostasis while concurrently protecting against RGD-containing toxins.

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Activation of Platelet αIIbβ3 by an Exogenous Peptide Corresponding to the Transmembrane Domain of αIIb

Cited by 52 publications

References 45 publications

Reconstruction of integrin activation

Reconstruction of integrin activation

Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment

Species differences in small molecule binding to αIIbβ3 are the result of sequence differences in 2 loops of the αIIb β propeller

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