The heparin binding domain of S-protein/vitronectin binds to complement components C7, C8, and C9 and perforin from cytolytic T-cells and inhibits their lytic activities

Tschopp, Jürg; Masson, Danièle; Schäfer, Sylvie; Peitsch, Manuel C.; Kt, Preissner

doi:10.1021/bi00411a029

Cited by 118 publications

(69 citation statements)

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“…41 Moreover, this finding is relevant to dry AMD, as vitronectin is a major component of drusen, a feature which correlates significantly with the early stage of AMD. 20 As vitronectin regulates complement activation by inhibiting the formation of MAC, 42 an increased amount of the protein suggests that a negative feed-back loop is activated to protect against uncontrolled complement activation.…”

Section: Discussionmentioning

confidence: 99%

Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Lueck

Wasmuth

Williams³

et al. 2011

Eye

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Purpose There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD. Methods For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography. Results Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC. Conclusions MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production.

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Section: Discussionmentioning

confidence: 99%

Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Lueck

Wasmuth

Williams³

et al. 2011

Eye

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“…Panel B shows the relative orientation of PAI-1-binding residues in the solution structure (blue) and x-ray structure (red). Residues identified to participate in PAI-1 binding by site-directed mutagenesis (17) are shown by side chains for Asp 22 , Leu 24 , Tyr 27 , Tyr 28 , and Asp 34 , and by highlighting the backbone region for Gly 12 . Three additional residues, Thr 10 , Phe 13 , and Glu 23 , were identified at the PAI-1-binding interface from the crystallography work (20).…”

Section: Figmentioning

confidence: 99%

“…Vitronectin can also associate with PAI-1 and assemble to form higher order complexes (10) that exhibit altered adhesive functions (11). Key to the adhesive functions of vitronectin are its interactions with cell-surface receptors including integrins and uPAR.A widely accepted model suggests that vitronectin is organized into functional domains that provide the broad repertoire necessary for binding to target ligands (12)(13)(14). We recently used computational methods to predict the structure of the three domains comprising vitronectin (15).…”

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confidence: 99%

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The Solution Structure of the N-terminal Domain of Human Vitronectin

Mayasundari¹,

Whittemore²,

Serpersu

et al. 2004

Journal of Biological Chemistry

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The three-dimensional structure of an N-terminal fragment comprising the first 51 amino acids from human plasma vitronectin, the somatomedin B (SMB) domain, has been determined by two-dimensional NMR approaches. An average structure was calculated, representing the overall fold from a set of 20 minimized structures. The core residues (18 -41) overlay with a root mean square deviation of 2.29 ؎ 0.62 Å. The N-and Cterminal segments exhibit higher root mean square deviations, reflecting more flexibility in solution and/or fewer long-range NOEs for these regions. Residues 26 -30 form a unique single-turn ␣-helix, the locus where plasminogen activator inhibitor type-1 (PAI-1) is bound. This structure of this helix is highly homologous with that of a recombinant SMB domain solved in a co-crystal with PAI-1 (Zhou, A., Huntington, J. A., Pannu, N. S., Carrell, R. W., and Read, R. J. (2003) Nat. Struct. Biol. 10, 541-544), although the remainder of the structure differs. Significantly, the pattern of disulfide cross-links observed in this material isolated from human plasma is altogether different from the disulfides proposed for recombinant forms. The NMR structure reveals the relative orientation of binding sites for cell surface receptors, including an integrin-binding site at residues 45-47, which was disordered and did not diffract in the co-crystal, and a site for the urokinase receptor, which overlaps with the PAI-1-binding site.Human vitronectin is a glycoprotein found in the circulation, where it contributes to hemostasis by regulating blood coagulation and fibrinolysis (1, 2). Vitronectin is also found in the ECM, 1 where it plays important roles in cell adhesion, pericellular proteolysis, tissue invasion, angiogenesis, and metastasis (3-7). The variety of functions of vitronectin in the two microenvironments is a manifestation of its ability to interact with numerous humoral and cellular proteins. An important binding partner for vitronectin is the serine protease inhibitor PAI-1, which also is found both in circulation and the ECM. Furthermore, it has different activities depending upon this localization; the anti-protease activity of PAI-1 that regulates thrombolysis in the circulation is targeted instead toward pericellular proteolysis when localized to the ECM or cell/matrix boundary. Vitronectin binds to PAI-1 with high affinity and stabilizes the inhibitor in its active conformation (8, 9). Vitronectin can also associate with PAI-1 and assemble to form higher order complexes (10) that exhibit altered adhesive functions (11). Key to the adhesive functions of vitronectin are its interactions with cell-surface receptors including integrins and uPAR.A widely accepted model suggests that vitronectin is organized into functional domains that provide the broad repertoire necessary for binding to target ligands (12)(13)(14). We recently used computational methods to predict the structure of the three domains comprising vitronectin (15). A threading algorithm gave high confidence predictions for the central domai...

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“…DISCUSSION SP-40,40 is a multi-functional protein as well as S-protein (vitronectin). The common activities of both proteins include regulation of the membrane attack complex of the complement [28][29][30] and binding to b-endorphin. 31,32) In this paper, I described another common activity of S-protein and SP-40,40 on PAI-1 stabilization.…”

Section: Fig 1 Sds-page and Western-blot Analysis Of Pai-1 · Pai-1-mentioning

confidence: 99%

SP-40,40 Is a Component of Plasminogen Activator Inhibitor-1-Binding Protein and Stabilizes Plasminogen Activator Inhibityor-1 Activity.

Choi-Miura

2001

Biological & Pharmaceutical Bulletin

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SP-40,40 is an 80-kDa glycoprotein consisting of two 40-kDa subunits (a-chain and b-chain). It is a multi-functional protein which modulates the membrane attack complex of the complement, [1][2][3] causes cell aggregation, 4) accelerates immune complex formation 5) and binds to b-endorphin.6)The induction of SP-40,40 synthesis in the hippocampi of patients with Alzheimer's disease has been reported, 7,8) and we have also reported the incorporation of SP-40,40 into senile plaque.9) It was also reported that SP-40,40 existed in serum as a minor component of high density lipoproteins. [10][11][12] From its structural similarity, SP-40,40 is thought to be a human counterpart of ram clusterin, which causes cell aggregation, 13) rat SGP-2, which participates in spermatogenesis, 14) rat TRPM-2, which is induced during programmed cell death (apoptosis), 15) quail T64, which is induced by src gene expression, 16) bovine GPIII, which is purified from the chromaffin granule membrane of adrenal medula 17) and canine gp80, which is a marker protein of apical secretion. 18)Plasminogen activator inhibitor-1 (PAI-1) is an unstable protein which binds to plasminogen activator (PA) and inhibits its activity. 19,20) It was reported that S-protein (vitronectin) bound to PAI-1 and stabilized its activity. 21,22) Declerck et al. purified PAI-1-binding protein (PAI-1-BP), and it was shown to consist of S-protein and unidentified 40-kDa protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. 23) From the functional similarity of S-protein and SP-40,40, e.g., inhibition of the complement system 1-3) and binding to b-endorphin, 6) we supposed that the unidentified 40-kDa protein might be SP-40,40. In this paper, I describe that PAI-1-BP consists of S-protein and SP-40,40, and that SP-40,40 stabilizes PAI-1 activity as well as S-protein does. MATERIALS AND METHODSMaterials Plasminogen, urine plasminogen activator (uPA) and fibrinogen were purchased from Sigma. Fibrinogen was cleaved with BrCN in 70% formic acid and dialyzed against distilled water as described by Verheijen et al. 24) S-2251 was obtained from Kabi. Recombinant tissue plasminogen activator (tPA) was kindly gifted from Yamanouchi Co., Ltd. Outdated human plasma was obtained from the Japanese Red Cross Tokyo Blood Center, Musashino, Tokyo.Purification of PAI-1 PAI-1 was purified from the culture medium of HT1080 (human fibrosarcoma cell) according to Andreasen et al.19) The cells were maintained as a monolayer culture in Dulbecco-modified Eagle's medium (Gibco) supplemented with 10% fetal bovine serum (Gibco) and 1 mM dexamethasone (Sigma). After the cells reached 80% confluence, the medium was changed to serum-free medium containing 1 mM dexamethasone, and the culture was continued for 3 d. PAI-1 (500 mg) was purified from 1 l of the serum-free conditioned medium using a Con A-Sepharose (20 ml, Pharmacia) column. Purified PAI-1 was activated in 12 M urea at 37°C for 30 min and dialyzed against PBS at 4°C overnight. Purific...

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The heparin binding domain of S-protein/vitronectin binds to complement components C7, C8, and C9 and perforin from cytolytic T-cells and inhibits their lytic activities

Cited by 118 publications

References 46 publications

Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

The Solution Structure of the N-terminal Domain of Human Vitronectin

SP-40,40 Is a Component of Plasminogen Activator Inhibitor-1-Binding Protein and Stabilizes Plasminogen Activator Inhibityor-1 Activity.

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