A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking

Sowmya, Gopichandran; Khan, Javed; Anand, Samyuktha; Ahn, Seong Beom; Baker, Mark S.; Ranganathan, Shoba

doi:10.1016/j.jsb.2014.01.001

Cited by 14 publications

(25 citation statements)

References 63 publications

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“…In the brain, integrins have been studied during development, where they participate in neuroblasts migration [30] and axonal and dendritic outgrowth, via their ability to interact with the ECM [31] . An interaction between uPAR and different integrin subunits, mostly β1, β3 and β6, has been described by biochemical and computational technics [32][33][34][35] . Because the β1 integrin subunit is the receptor for fibronectin [36][37][38] , and since fibronectin is required in our system for uPA/uPAR to promote axonal regeneration, then we postulated that β1 integrin was the co-receptor that mediates the effect of uPA/uPAR on neurorepair.…”

Section: Membrane Recruitment Of ß1-integrin Mediates Upa/upar-inducementioning

confidence: 99%

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Merino

Diaz

Yepes

2017

Receptor Clin Invest

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Despite the fact that ischemic stroke has been considered a leading cause of mortality in the world, recent advances in our understanding of the pathophysiological mechanisms underlying the ischemic injury and the treatment of acute ischemic stroke patients have led to a sharp decrease in the number of stroke deaths. However, this decrease in stroke mortality has also led to an increase in the number of patients that survive the acute ischemic injury with different degrees of disability. Unfortunately, to this date we do not have an effective therapeutic strategy to promote neurological recovery in these growing population of stroke survivors. Cerebral ischemia not only causes the destruction of a large number of axons and synapses but also activates endogenous mechanisms that promote the recovery of those neurons that survive its harmful effects. Here we review experimental evidence indicating that one of these mechanisms of repair is the binding of the serine proteinase urokinase-type plasminogen activator (uPA) to its receptor (uPAR) in the growth cones of injured axons. Indeed, the binding of uPA to uPAR in the periphery of growth cones of injured axons induces the recruitment of β1-integrin to the plasma membrane, β1-integrin-mediated activation of the small Rho GTPase Rac1, and Rac1-induced axonal regeneration. Furthermore, we found that this process is modulated by the low density lipoprotein receptor-related protein (LRP1). The data reviewed here indicate that the uPA-uPAR-LRP1 system is a potential target for the development of therapeutic strategies to promote neurological recovery in acute ischemic stroke patients.Keywords: Urokinase-type plasminogen activator (uPA); urokinase-type plasminogen activator receptor (uPAR); plasmin; cerebral ischemia; neurorepair; low density lipoprotein receptor-related protein 1 (LRP1)To cite this article: Paola Merino, et al. Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain.

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Section: Membrane Recruitment Of ß1-integrin Mediates Upa/upar-inducementioning

confidence: 99%

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Merino

Diaz

Yepes

2017

Receptor Clin Invest

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“…X-ray crystallographic structures of specific domains of other heterodimers such as αvβ3 and αIIbβ3 are available [89], and these have recently enabled Sowmya et al to perform structural analyses that relate to the functional significance of these ECM receptors [90]. They performed composite homology modelling to construct a 3D structural model of the large membrane protein αvβ6•uPAR complex that included the transmembrane and cytoplasmic domains of both integrin subunits [90]. Modelled structures were subjected to iterations of stereo-chemical refinements drawn from a pool of randomised potential starting conformations and made to satisfy spatial restraints [90].…”

Section: αVβ6 Interacts With Domain III Of Upar Through the αV Subunitmentioning

confidence: 99%

“…They performed composite homology modelling to construct a 3D structural model of the large membrane protein αvβ6•uPAR complex that included the transmembrane and cytoplasmic domains of both integrin subunits [90]. Modelled structures were subjected to iterations of stereo-chemical refinements drawn from a pool of randomised potential starting conformations and made to satisfy spatial restraints [90]. The best structural model, based upon lowest current energy and best objective function, was subjected to structural quality assessment [90], providing the first glimpse into the structure of the heterodimer and its complex with uPAR.…”

Section: αVβ6 Interacts With Domain III Of Upar Through the αV Subunitmentioning

confidence: 99%

“…Modelled structures were subjected to iterations of stereo-chemical refinements drawn from a pool of randomised potential starting conformations and made to satisfy spatial restraints [90]. The best structural model, based upon lowest current energy and best objective function, was subjected to structural quality assessment [90], providing the first glimpse into the structure of the heterodimer and its complex with uPAR. This showed that approximately 11 % of αv and β6 ectodomain residues participated in the αv•β6 interaction and thus formed an obligatory protein-protein interaction complex as the respective subunits were unstable in their monomeric states, and thus had no independent existence [90].…”

Section: αVβ6 Interacts With Domain III Of Upar Through the αV Subunitmentioning

confidence: 99%

“…The best structural model, based upon lowest current energy and best objective function, was subjected to structural quality assessment [90], providing the first glimpse into the structure of the heterodimer and its complex with uPAR. This showed that approximately 11 % of αv and β6 ectodomain residues participated in the αv•β6 interaction and thus formed an obligatory protein-protein interaction complex as the respective subunits were unstable in their monomeric states, and thus had no independent existence [90]. Sowmya et al also suggested that the αv and β6 subunits underwent large conformational dynamics upon assembly; after which, polar interactions formed the dominant forces that promoted αv•β6 subunit interface formation as well as protein•protein interaction at the heterodimer surface [90].…”

Section: αVβ6 Interacts With Domain III Of Upar Through the αV Subunitmentioning

confidence: 99%

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Integrin αvβ6 sets the stage for colorectal cancer metastasis

Cantor

Cheruku

Nice

et al. 2015

Cancer Metastasis Rev

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The β6 subunit of the αvβ6 integrin heterodimer has long been an enigma in cancer biology though recent research has provided many new insights into its biology. Collectively, these findings include discovery of the transcriptional, translational and cell biological mechanisms by which β6 acts, the identification of the cellular influences β6 exerts upon the cell proteome, the characterisation of multiple β6-centric pro-metastatic signalling systems and the search for pharmacological therapies (industry and academia) targeted against β6. Once expressional restriction is overcome in early colorectal cancer (CRC), epithelial cell surface restricted αvβ6 can physically interact with, and activate, known oncoproteins, and has the potential to enable the cross-talk through non-canonical signal transduction pathways, resulting in the adoption of an invasive/metastatic phenotype. This recent research has identified numerous interconnections and potential feedback loops, highlighting the fact that the expression of the β6 subunit may initiate a cascade of downstream effects on the CRC cell rather than acting through a single mechanism. We here review these recent studies and postulate that the existence of a cell surface uPAR/αvβ6/TGFβ "metastasome" interactome in/on a proportion of colorectal cancer cells, where β6 expression sequesters and activates multiple systems at the invasive front of tumour lesions, promoting cancer metastasis and hence explaining why β6 has been correlated with reduced patient survival in CRC.

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Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

Bugatti

Bruno

Sartori

et al. 2020

Chemistry A European J

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In recognition of the key role played by integrins in several life-threatening dysfunctions,t he search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimeticswith attracting a V b 3 integrin affinity and selectivity,t he designa nd straightforward synthesis of 18 new AmpRGD chemotypes bearinga dditional structuralv ariants were herein implemented, to shift toward peptide-like a V b 6 integrin targeted binders. The ligand competence of the synthesized products toward a V b 6 was evaluatedi nc ompetitive bindinga ssays on isolated receptors, and a V b 6 /a V b 3 selectivity was determined for as ubgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.

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A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking

Cited by 14 publications

References 63 publications

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Integrin αvβ6 sets the stage for colorectal cancer metastasis

Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

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A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking

Cited by 14 publications

References 63 publications

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Integrin αvβ6 sets the stage for colorectal cancer metastasis

Shifting Towards αVβ6 Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

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Product

Resources

About

Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics