Activation of Integrin αIIbß3 by Modulation of Transmembrane Helix Associations

Li, Renhao; Mitra, N. K.; Gratkowski, Holly; Vilaire, Gaston; Litvinov, Rustem I.; Nagasami, Chandrasekaran; Weisel, John W.; Lear, James D.; DeGrado, William F.; Bennett, Joel S.

doi:10.1126/science.1079441

Cited by 282 publications

(293 citation statements)

References 29 publications

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“…This switch likely involves changes in integrin conformation and/or proximity. [188] Integrins are proposed to adopt at least two conformational states: a bent inactive state and an extended active state. [187] In addition, they can undergo changes in receptor proximity, which can be induced either by interaction with ligand (an "outside-in" change) or by cellular activation (an "inside-out" change).…”

Section: 1a Integrins-integrinsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: 1a Integrins-integrinsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…To this end, we used the TM mutation G792N, shown in vertebrates to enhance clustering by disrupting packing of a and b TM helices (G708 in b3; Li et al, 2003). The effects of these mutations on integrin function have been well characterized in vitro by various means, and for most, structural data in addition to activity assays support the proposed mechanistic effects.…”

Section: Mutational Analysis Of Drosophila B-integrinmentioning

confidence: 99%

Distinct regulatory mechanisms control integrin adhesive processes during tissue morphogenesis

Pines

Fairchild

Tanentzapf

2010

Developmental Dynamics

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Cell adhesion must be precisely regulated to enable both dynamic morphogenetic processes and the subsequent transition to stable tissue maintenance. Integrins link the intracellular cytoskeleton and extracellular matrix, relaying bidirectional signals across the plasma membrane. In vitro studies have demonstrated that multiple mechanisms control integrin-mediated adhesion; however, their roles during development are poorly understood. We used mutations that activate or deactivate specific functions of vertebrate b-integrins in vitro to investigate how perturbing Drosophila bPS-integrin regulation in developing embryos affects tissue morphogenesis and maintenance. We found that morphogenetic processes use various b-integrin regulatory mechanisms to differing degrees and that conformational changes associated with outside-in activation are essential for developmental integrin functions. Long-term adhesion is also sensitive to integrin dysregulation, suggesting integrins must be continuously regulated to support stable tissue maintenance. Altogether, in vivo phenotypic analyses allowed us to identify the importance of various b-integrin regulatory mechanisms during different morphogenetic processes. Developmental Dynamics 240:36-51,

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“…Previous studies (30) have shown that the introduction of an Asn at this position activated ␣IIb␤3 and suggested that it did so by forming hydrogen bonds that favor ␤3 homo-oligomerization. The Ser substitution could also, in principle, lead to enhanced ␤3-␤3 interactions through such a mechanism.…”

Section: Mutagenesis Of Predicted Tm Packing Residuesmentioning

confidence: 99%

Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

Partridge

Liu²,

Kim

et al. 2005

Journal of Biological Chemistry

141

161

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Regulated changes in the affinity of integrin adhesion receptors ("activation") play an important role in numerous biological functions including hemostasis, the immune response, and cell migration. Physiological integrin activation is the result of conformational changes in the extracellular domain initiated by the binding of cytoplasmic proteins to integrin cytoplasmic domains. The conformational changes in the extracellular domain are likely caused by disruption of intersubunit interactions between the ␣ and ␤ transmembrane (TM) and cytoplasmic domains. Here, we reasoned that mutation of residues contributing to ␣/␤ interactions that stabilize the low affinity state should lead to integrin activation. Thus, we subjected the entire intracellular domain of the ␤3 integrin subunit to unbiased random mutagenesis and selected it for activated mutants. 25 unique activating mutations were identified in the TM and membrane-proximal cytoplasmic domain. In contrast, no activating mutations were identified in the more distal cytoplasmic tail, suggesting that this region is dispensable for the maintenance of the inactive state. Among the 13 novel TM domain mutations that lead to integrin activation were several informative point mutations that, in combination with computational modeling, suggested the existence of a specific TM helix-helix packing interface that maintains the low affinity state. The interactions predicted by the model were used to identify additional activating mutations in both the ␣ and ␤ TM domains. Therefore, we propose that helical packing of the ␣ and ␤ TM domains forms a clasp that regulates integrin activation.Integrin heterodimers are essential for the development and functioning of multicellular animals, because they mediate cell migration and cell adhesion and can influence gene expression and cell proliferation (1). All of the integrin heterodimers are composed of single pass Type I transmembrane (TM) 1 protein subunits ␣ and ␤. A central feature of these receptors is their capacity for rapid changes in their adhesive function mediated by changes in their ligand binding affinity, operationally defined here as "activation." The prototypical integrin, platelet ␣IIb␤3, is activated through interactions of the cytoplasmic integrin tails (ϳ20 and 47 residues for ␣ and ␤ tails, respectively) with intracellular proteins such as talin (2). These interactions initiate a long-range conformational change in the large extracellular domains (Ͼ700 residues each), resulting in high affinity binding of fibrinogen, von Willebrand factor, and fibronectin and consequently platelet aggregation and adherence to the vessel wall (1).Initial mutational studies suggested that a salt bridge between ␣IIbArg 995 and ␤3Asp 723 helps maintain the integrin in the low affinity state by forming part of an interactive face between ␣ and ␤ subunit cytoplasmic domains (3). Protein engineering studies from Springer laboratory have further advanced the idea that specific integrin ␣/␤ interactions maintain the low affinity conform...

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Activation of Integrin αIIbß3 by Modulation of Transmembrane Helix Associations

Cited by 282 publications

References 29 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

Distinct regulatory mechanisms control integrin adhesive processes during tissue morphogenesis

Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State

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