The presence of methionine or threonine at position 381 in vitronectin is correlated with proteolytic cleavage at arginine 379.

Tollefsen, Douglas M.; Weigel, C; Kabeer, Mustafa H.

doi:10.1016/s0021-9258(19)38738-1

Cited by 39 publications

(11 citation statements)

References 38 publications

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“…In contrast, we found decreased plasma levels of both VN isoforms prior to preeclampsia with SGA. Differences in the prevalence of a single nucleotide polymorphism near the cleavage site of the 75 kd VN (residue 381) can alter the ratio of circulating 75-and 65-kd V. 19,20 No association with preeclampsia has been investigated to date for polymorphisms of the VN gene.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Processing of Plasma Vitronectin and High-Molecular-Weight Kininogen Precedes the Onset of Preeclampsia

et al. 2009

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To date, there is no reliable test to identify women in early pregnancy at risk of developing preeclampsia. Difference gel electrophoresis (DIGE) identified the plasma proteins vitronectin (VN) and high-molecular-weight kininogen (HK) in association with preeclampsia. In a longitudinal proteomics study, the plasma of preeclamptic patients (n = 6) was compared to healthy control participants (n = 6) before the onset of preeclampsia (week 20) and at the time of presentation with clinical disease (weeks 33-36). The 75-kd single-chain VN molecule increased 1.6- to 1.9-fold in preeclampsia, whereas the 65-kd moiety of the 2-chain VN molecule decreased 1.5- to 1.7-fold compared to healthy controls (P < .05). Immunoblots revealed differences in proteolytic processing of VN and/or HK in women who develop preeclampsia or preeclampsia further complicated by small-for-gestational-age. Vitronectin and HK may prove to be useful as early markers of fibrinolytic activity and neutrophil activation, which are known to be associated with preeclampsia.

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Section: Discussionmentioning

confidence: 99%

Aberrant Processing of Plasma Vitronectin and High-Molecular-Weight Kininogen Precedes the Onset of Preeclampsia

et al. 2009

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“…During biosynthesis, removal of a 19-residue signal peptide yields the mature vitronectin chain of 459 amino acids (72 kDa); further processing of mature vitronectin by proteolytic cleavage at position 379 can produce a disulfide cross-linked form comprising 62 and 10 kDa subunits. A genetic polymorphism encoding Thr or Met as residue 381 controls the propensity of vitronectin to be cleaved to the two-chain form; however, the single- and two-chain variants appear to be functionally indistinguishable . X-ray scattering and computational predictions for the full-length protein, along with experimental structures determined for the N-terminal somatomedin B (SMB) domain, have led to a proposed domain organization and three-dimensional models for vitronectin. ,− This domain structure is illustrated in Figure .…”

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confidence: 99%

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

et al. 2019

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Small-angle neutron scattering (SANS) measurements were pursued to study human vitronectin, a protein found in tissues and the circulation that regulates cell adhesion/ migration and proteolytic cascades that govern hemostasis and pericellular proteolysis. Many of these functions occur via interactions with its binding partner, plasminogen activator inhibitor-1 (PAI-1), the chief inhibitor of proteases that lyse and activate plasminogen. We focused on a region of vitronectin that remains uncharacterized from previous X-ray scattering, nuclear magnetic resonance, and computational modeling approaches and which we propose is involved in binding to PAI-1. This region, which bridges the N-terminal somatomedin B (SMB) domain with a large central β-propeller domain of vitronectin, appears unstructured and has characteristics of an intrinsically disordered domain (IDD). The effect of osmolytes was evaluated using circular dichroism and SANS to explore the potential of the IDD to undergo a disorder-to-order transition. The results suggest that the IDD favors a more ordered structure under osmotic pressure; SANS shows a smaller radius of gyration (R g ) and a more compact fold of the IDD upon addition of osmolytes. To test whether PAI-1 binding is also coupled to folding within the IDD structure, a set of SANS experiments with contrast variation were performed on the complex of PAI-1 with a vitronectin fragment corresponding to the N-terminal 130 amino acids (denoted the SMB-IDD because it contains the SMB domain and IDD in linear sequence). Analysis of the SANS data using the Ensemble Optimization Method confirms that the SMB-IDD adopts a more compact configuration when bound to PAI-1. Calculated structures for the PAI-1:SMB-IDD complex suggest that the IDD provides an interaction surface outside of the primary PAI-1-binding site located within the SMB domain; this binding is proposed to lead to the assembly of higher-order structures of vitronectin and PAI-1 commonly found in tissues.

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“…Their study, however, used a truncated version of VTN_rs704: C, apparently lacking the short chain peptide of the rs704-dependent protein cleavage product, although the short fragment in VTN_rs704: C remains bound to the protein by a disulphide bond in vivo [ 8 , 67 , 68 ] and likely influences the folding or accessibility of putative binding sites for PAI-1. The stronger binding of VTN_rs704: T to PAI-1 may be explained by the rs704-dependent amino acid change (Thr400Met), which causes altered protein folding and processing [ 32 , 69 ], potentially influencing accessibility to the PAI-1 interaction site. Alternatively, the altered binding properties could reveal specificities in the PAI-1-mediated assembly into higher-order complexes [ 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

“…Strep-tagged PAI-1 was recognized as a major molecular weight species slightly above 55 kDa, with an occasionally appearing additional lower molecular weight, as reported earlier for purified PAI-1 [ 30 , 31 ]. Purified strep-tagged VTN_rs704: C and VTN_rs704: T showed stains with a molecular weight of about 75 kDa and 65 kDa, as previously described [ 8 , 32 ].…”

Section: Methodsmentioning

confidence: 98%

“…Arrowheads indicate different fractions of recombinant vitronectin after its proteolytic cleavages (white arrows: cleavage between aa Arg398 and Ala399, black arrows: cleavage between aa Arg380 and Ser381) by endogenously expressed endoproteases. In contrast to VTN_rs704: C that stains as a mixture of a single polypeptide chain (about 75 kDa) and a clipped form (two chains of 65 and 10 kDa, held together by disulfide bonds, with the 10 kDa chain not detectable within this experimental setup), VTN_rs704: T is less susceptible to the proteolytic cleavage at Arg398-Ala399 indicated by a higher proportion of the uncleaved 75 kDa protein [ 8 , 32 ]. Molecular weights of approximately 63 kDa (black arrows) depict vitronectin fragments resulting from cleavage at Arg380-Ser381, as described in [ 50 ].…”

Section: Figurementioning

confidence: 99%

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Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

Biasella

Strunz

Kiel

et al. 2022

Cells

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The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD.

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The presence of methionine or threonine at position 381 in vitronectin is correlated with proteolytic cleavage at arginine 379.

Cited by 39 publications

References 38 publications

Aberrant Processing of Plasma Vitronectin and High-Molecular-Weight Kininogen Precedes the Onset of Preeclampsia

Aberrant Processing of Plasma Vitronectin and High-Molecular-Weight Kininogen Precedes the Onset of Preeclampsia

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

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