The three-fingered protein domain of the human genome

Gałat, Andrzej

doi:10.1007/s00018-008-8473-8

Cited by 44 publications

(64 citation statements)

References 89 publications

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“…Although a plethora of ligands have been proposed for uPAR, uPA binding will most likely only influence those binding sites that localize to DI and the interface between DI and DII in particular. uPAR is encoded by a small gene cluster containing at least six homologous proteins containing 2-4 LU-domains (13,21). Interestingly, these multidomain homologs all possess an atypical DI, which is lacking one particular consensus disulfide that is essential for the stability of the corresponding single domain proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The ligand-binding part of the glycolipid-anchored uPAR (20) comprises three homologous, three-fingered modules designated DI, DII, and DIII, which belong to the Ly6/uPAR/␣-neurotoxin (LU) protein domain family as defined by four con-served disulfide bonds (21,22). The structures of several uPAR complexes have been solved by x-ray crystallography, including those with a synthetic antagonist peptide (23), the amino-terminal fragment of uPA (ATF) (24 -26), and the ternary complex with ATF and the SMB domain from vitronectin (27).…”

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confidence: 99%

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A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

Mertens

Kjærgaard

Mysling

et al. 2012

Journal of Biological Chemistry

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Background:The urokinase receptor (uPAR) is a modular receptor containing three LU domains. Results: Ligand-free uPAR is inherently flexible with a detached N-terminal domain (DI). Conclusion: Allosteric regulation of uPAR is driven by uPA-induced compaction of the intact receptor and a concomitant stabilization of DI. Significance: This flexibility and ligand-induced allostery are expected to impact future studies on uPAR function and targeted intervention.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

Mertens

Kjærgaard

Mysling

et al. 2012

Journal of Biological Chemistry

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“…The human genome codes for 45 members of the Ly6 superfamily (Galat, 2008). These include 12 TGFβ receptors, the ectodomains of which adopt the three-finger fold, but also many glycosylphosphatidylinositol (GPI)-anchored proteins and soluble ligands.…”

Section: Introductionmentioning

confidence: 99%

boudinis required for septate junction organisation inDrosophilaand codes for a diffusible protein of the Ly6 superfamily

et al. 2009

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The Ly6 superfamily, present in most metazoan genomes, codes for different cell-surface proteins and secreted ligands containing an extracellular motif called a Ly6 domain or three-finger domain. We report the identification of 36 novel genes coding for proteins of this family in Drosophila. One of these fly Ly6 proteins, coded by the gene boudin (bou), is essential for tracheal morphogenesis in the fly embryo and contributes to the maintenance of the paracellular barrier and the organisation of the septate junctions in this tissue. Bou, a glycosylphosphatidylinositol anchored membrane protein, is also required for septate junction organisation in epithelial tissues and in the chordotonal organ glial cells, but not in the central nervous system. Our study reveals interesting parallelisms between the Ly6 proteins of flies and vertebrates, such as the CD59 antigen. Similarly to this human protein, Bou travels from cell to cell associated with extracellular particles and, consistently, we show that it is required in a non-cellautonomous fashion. Our work opens the way for future studies addressing the function of Ly6 proteins using Drosophila as a model system.

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“…The far majority of proteins belonging to this domain family contain only a single copy of the LU module, as exemplified by the glycolipid-anchored CD59, the extracellular ligand binding domain in the TGF-␤ receptors, and the diverse group of secreted snake venom ␣-neurotoxins (13). In the human genome, five genes are recognized so far to encode proteins with multiple LU domains, and these are all confined to a small gene cluster located on chromosome 19q13 (14).…”

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confidence: 99%

Conformational Regulation of Urokinase Receptor Function

Gårdsvoll

Jacobsen

Kriegbaum

et al. 2011

Journal of Biological Chemistry

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The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the ␤-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the ␤-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.Timely controlled cell migration is a decisive factor for a plethora of important biological processes that occur during development and adulthood. Controlled cell migration is thus intimately involved in both maintenance and dynamic remodeling of tissue architectures during, e.g. wound healing and mammary gland development (1). These processes are executed and tightly regulated via a complicated cross-talk between specific cell surface receptors (e.g. integrins) and insoluble protein components deposited in the extracellular matrix. The extracellular matrix is nonetheless thought to play a dual role in regulating cell migration, as it provides both the focal adhesion sites required for cellular traction and opposes migration by generating physical barriers (2, 3). Cell migration in vivo, therefore, requires a coordinated regulation of extracellular matrix proteolysis, adhesion, and signaling (4). The urokinase-type plasminogen activator receptor (uPAR) 2 may allegedly assist a rendezvous between these functions, as it has the potential to exert control at all three levels. Besides being responsible for focalizing uPA-mediated plasminogen activation on cell surfaces (5-7), uPAR also facilitates adherence to vitronectin embedded in the extracellular matrix (8 -10), and as a consequence, it promotes intracellular signaling (4, 11).The glycolipid-anchored uPAR is a modular glycoprotein composed of three homologous Ly6/uPAR-type (LU) protein domain repeats (5, 12). The far majority of proteins belonging to this domain family contain only a single copy of the LU module, as exemplified by the glycolipid-anchored CD59, the extracellular ligand binding domain in the TGF-␤ receptors, and the diverse group of secreted snake venom ␣-neurotoxins (13). In the human genome, five genes are recognized so far to encode proteins with multiple LU domains, and these are all confined to a small ...

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The three-fingered protein domain of the human genome

Cited by 44 publications

References 89 publications

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

boudinis required for septate junction organisation inDrosophilaand codes for a diffusible protein of the Ly6 superfamily

Conformational Regulation of Urokinase Receptor Function

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