Insights into Protein–Ligand Interactions in Integrin Complexes: Advances in Structure Determinations

Zheng, Ya-Jun; Leftheris, Katerina

doi:10.1021/acs.jmedchem.9b01869

Cited by 29 publications

(20 citation statements)

References 143 publications

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“…Continuous efforts by employing combination of structural tools (Cryo‐EM, X‐ray crystallography and NMR spectroscopy) and interface‐based mutagenesis studies will allow us to gain more precise insight into the regulation of such complex and dynamic network. Currently, many drugs including monoclonal antibodies, peptide‐mimetics and small compounds have been developed to target the extracellular domains of integrin receptors to treat related human diseases 107,108 . Intracellular interactions summarized here also play pivotal roles in the regulation of integrin signaling.…”

Section: Resultsmentioning

confidence: 99%

Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

2020

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Focal adhesions (FAs) are integrin‐containing protein complexes regulated by a network of hundreds of protein–protein interactions. They are formed in a spatiotemporal manner upon the activation of integrin transmembrane receptors, which is crucial to trigger cell adhesion and many other cellular processes including cell migration, spreading and proliferation. Despite decades of studies, a detailed molecular level understanding on how FAs are organized and function is lacking due to their highly complex and dynamic nature. However, advances have been made on studying key integrin activators, talin and kindlin, and their associated proteins, which are major components of nascent FAs critical for initiating the assembly of mature FAs. This review will discuss the structural and functional findings of talin and kindlin and their immediate interaction network, which will shed light upon the architecture of nascent FAs and how they act as seeds for FA assembly to dynamically regulate diverse adhesion‐dependent physiological and pathological responses.

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Section: Resultsmentioning

confidence: 99%

Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

2020

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“…Ligand-induced conformational propagation and receptor clustering trigger numerous intracellular signaling cascades after assembly of focal signaling complexes at the cytoplasmic face of the cell membrane, which may include kinases and adaptors. Nearly 60 proteins have been identified as constituents of this adhesome ( 19 ).…”

Section: Integrins and Cr3: Function Through Flexibilitymentioning

confidence: 99%

The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

2021

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The β2-integrin receptor family has a broad spectrum of physiological functions ranging from leukocyte adhesion, cell migration, activation, and communication to the phagocytic uptake of cells and particles. Among the members of this family, complement receptor 3 (CR3; CD11b/CD18, Mac-1, αMβ2) is particularly promiscuous in its functional profile and ligand selectivity. There are close to 100 reported structurally unrelated ligands for CR3, and while many ligands appear to cluster at the αMI domain, molecular details about binding modes remain largely elusive. The versatility of CR3 is reflected in its functional portfolio, which includes prominent roles in the removal of invaders and cell debris, induction of tolerance and synaptic pruning, and involvement in the pathogenesis of numerous autoimmune and chronic inflammatory pathologies. While CR3 is an interesting therapeutic target for immune modulation due to these known pathophysiological associations, drug development efforts are limited by concerns of potential interference with host defense functions and, most importantly, an insufficient molecular understanding of the interplay between ligand binding and functional impact. Here, we provide a systematic summary of the various interaction partners of CR3 with a focus on binding mechanisms and functional implications. We also discuss the roles of CR3 as an immune receptor in health and disease, as an activation marker in research and diagnostics, and as a therapeutic target.

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“…Deficiency of GPVI (Kato et al, 2003) or its inhibition by antibodies or pharmaceuticals (Nieswandt et al, 2001;Martins Lima et al, 2019) affect thrombus formation, although hemostasis, measured as bleeding time, is affected only mildly. In contrast to GPVI, the other collagen receptor on platelets, α2β1 integrin, belongs to the large family of integrins, consisting of two non-covalently associated subunits, α and β (Madamanchi et al, 2014;Zheng and Leftheris, 2020). The two integrin chains jointly form a globular head domain, which harbors the ligand binding site (Arnaout et al, 2005).…”

Section: Platelets the Cellular Players In Hemostasismentioning

confidence: 99%

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Obermann

Brockhaus

Eble

2021

Front. Cell Dev. Biol.

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Although platelets and the coagulation factors are components of the blood system, they become part of and contribute to the tumor microenvironment (TME) not only within a solid tumor mass, but also within a hematogenous micrometastasis on its way through the blood stream to the metastatic niche. The latter basically consists of blood-borne cancer cells which are in close association with platelets. At the site of the primary tumor, the blood components reach the TME via leaky blood vessels, whose permeability is increased by tumor-secreted growth factors, by incomplete angiogenic sprouts or by vasculogenic mimicry (VM) vessels. As a consequence, platelets reach the primary tumor via several cell adhesion molecules (CAMs). Moreover, clotting factor VII from the blood associates with tissue factor (TF) that is abundantly expressed on cancer cells. This extrinsic tenase complex turns on the coagulation cascade, which encompasses the activation of thrombin and conversion of soluble fibrinogen into insoluble fibrin. The presence of platelets and their release of growth factors, as well as fibrin deposition changes the TME of a solid tumor mass substantially, thereby promoting tumor progression. Disseminating cancer cells that circulate in the blood stream also recruit platelets, primarily by direct cell-cell interactions via different receptor-counterreceptor pairs and indirectly by fibrin, which bridges the two cell types via different integrin receptors. These tumor cell-platelet aggregates are hematogenous micrometastases, in which platelets and fibrin constitute a particular TME in favor of the cancer cells. Even at the distant site of settlement, the accompanying platelets help the tumor cell to attach and to grow into metastases. Understanding the close liaison of cancer cells with platelets and coagulation factors that change the TME during tumor progression and spreading will help to curb different steps of the metastatic cascade and may help to reduce tumor-induced thrombosis.

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Insights into Protein–Ligand Interactions in Integrin Complexes: Advances in Structure Determinations

Cited by 29 publications

References 143 publications

Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

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