Conformational changes in plasminogen, their effect on activation, and the agents that modulate activation rates — a review

Markus, Gabor

doi:10.1016/s0268-9499(96)80082-8

Cited by 46 publications

(70 citation statements)

References 73 publications

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“…2 C and E). The open form plasminogen is a better substrate for activation (37), and, given that plasminogen activators can activate single-chain HGF͞SF, preferential cleavage of the open form may also occur with single-chain HGF͞SF. As for receptor binding, the closed form of single-chain HGF͞SF is clearly unable to bind MET with both the nk1 and sp domains because of steric hindrance (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Gherardi

Sandin

Petoukhov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

198

194

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The polypeptide growth factor, hepatocyte growth factor͞scatter factor (HGF͞SF), shares the multidomain structure and proteolytic mechanism of activation of plasminogen and other complex serine proteinases. HGF͞SF, however, has no enzymatic activity. Instead, it controls the growth, morphogenesis, or migration of epithelial, endothelial, and muscle progenitor cells through the receptor tyrosine kinase MET. Using small-angle x-ray scattering and cryoelectron microscopy, we show that conversion of pro(single-chain)-HGF͞SF into the active two-chain form is associated with a major structural transition from a compact, closed conformation to an elongated, open one. We also report the structure of a complex between two-chain HGF͞SF and the MET ectodomain (MET928) with 1:1 stoichiometry in which the N-terminal and first kringle domain of HGF͞SF contact the face of the seven-blade ␤-propeller domain of MET harboring the loops connecting the ␤-strands b-c and d-a, whereas the C-terminal serine proteinase homology domain binds the opposite ''b'' face. Finally, we describe a complex with 2:2 stoichiometry between two-chain HGF͞SF and a truncated form of the MET ectodomain (MET567), which is assembled around the dimerization interface seen in the crystal structure of the NK1 fragment of HGF͞SF and displays the features of a functional, signaling unit. The study shows how the proteolytic mechanism of activation of the complex proteinases has been adapted to cell signaling in vertebrate organisms, offers a description of monomeric and dimeric ligand-receptor complexes, and provides a foundation to the structural basis of HGF͞SF-MET signaling.cell signaling ͉ plasminogen ͉ serine proteinases ͉ kringle ͉ x-ray scattering H epatocyte growth factor͞scatter factor (HGF͞SF) (1-6) are vertebrate-specific polypeptide growth factors with a domain structure related to that of plasminogen (7). Interest in HGF͞SF and its receptor MET (8) stems from unique biological roles in embryogenesis (9-11), tissue regeneration (12, 13), and cancer (14). These activities have led to a strong interest in the structure of the molecules as this knowledge may underpin the development of MET-based therapeutics.HGF͞SF consists of six domains: an N-terminal domain (n), four copies of the kringle domain (k1-k4), and a C-terminal domain (sp) structurally related to the catalytic domain of serine proteinases (Fig. 1A). The factor is synthesized as a precursor protein (pro-or single-chain HGF͞SF) and is proteolytically processed to a two-chain form by cleavage of the linker connecting the k4 and sp domains ( Fig. 1 A and B). Single-chain HGF͞SF binds MET (15, 16) but is unable to induce biological responses, for example, dispersion of MDCK cell colonies, even at concentrations 100-fold higher than two-chain HGF͞SF (Fig. 1 C-E).MET is also synthesized as a single-chain precursor that is cleaved by furin yielding an N-terminal ␣-chain and a C-terminal ␤-chain. The MET ectodomain consists of two moieties: the large, N-terminal sema domain, which is responsible f...

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Section: Discussionmentioning

confidence: 99%

Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Gherardi

Sandin

Petoukhov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

198

194

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“…that, in the absence of lysyl-type ligands, -60-80% of Glul-Pgn assumes a compact, "closed' shape while the rest is in an extended or "open" conformation (Markus, 1996 (Marshall et al, 1994) and -240 (Mangel et al, 1990), respectively, on the basis of the equilibrium open/close (= [K]/[K-NTP]) ratios given above and the estimated molecular volume, one obtains 0.47 < K, < 17.5 mM". Hence, the 2.3 < K, < 6.2 mM" values we have determined via 'H-NMR for the binding of CB-NTP to the isolated, intact kringles fall within range of the affinities that one may estimate from the independent data.…”

Section: Discussionmentioning

confidence: 99%

Structural/functional properties of the Glu1‐HSer57 N‐terminal fragment of human plasminogen: Conformational characterization and interaction with kringle domains

Martí

Carreño

et al. 1998

Protein Science

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The Glul-Val79 N-terminal peptide (NTP) domain of human plasminogen (Pgn) is followed by a tandem array of five kringle (K) structures of -9 kDa each. K1, K2, K4, and K5 contain each a lysine-binding site (LBS). Pgn was cleaved with CNBr and the Glul-HSer57 N-terminal fragment (CB-NTP) isolated. In addition, the Ile27-Ile56 peptide (L-NTP) that spans the doubly S-S bridged loop segment of NTP was synthesized. Pgn kringles were generated either by proteolytic fragmentation of Pgn (K4, K5) or via recombinant gene expression (rK1, rK2, and rK3). Interactions of CB-NTP with each of the Pgn kringles were monitored by 'H-NMR at 500 MHz and values for the equilibrium association constants (K,) determined: rK1, K, -4.6 m"' ; rK2, K, -3.3 mM"; K4, KO -6.2 m"' ; K5, KO -2.3 mM". Thus, the lysine-binding kringles interact with CB-NTP more strongly than with Ne-acetyl-L-lysine methyl ester ( K , < 0.6 mM"), which reveals specificity for the NTP. In contrast, CB-NTP does not measurably interact with rK3, which is devoid of a LBS.CB-NTP and L-NTP 'H-NMR spectra were assigned and interproton distances estimated from 'H-'H Overhauser (NOESY) experiments. Structures of L-NTP and the Glul-Ile27 segment of CB-NTP were computed via restrained dynamic simulated annealing/energy minimization (SA/EM) protocols. Conformational models of CB-NTP were generated by joining the two (sub)structures followed by a round of constrained SA/EM. Helical turns are indicated for segments 6-9, 12-16, 28-30, and 45-48. Within the Cys34-Cys42 loop of L-NTP, the structure of the Glu-Glu-AspGlu-Glu39 segment appears to be relatively less defined, as is the case for the stretch containing Lys50 within the Cys42-Cys54 segment, consistent with the latter possibly interacting with kringle domains in intact Glul-Pgn. Overall, the CB-NTP and L-NTP fragments are of low regular secondary structure content-as indicated by UV-CD spectraand exhibit fast amide 'H-2H exchange in 2H20, suggestive of high flexibility.Keywords: kringle domains; plasminogen activation peptide; plasminogen N-terminal peptide; preactivation peptide structure Reprint requests to: M. Llinas, Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; e-mail: Ilinas+ @andrew.cmu.edu. Abbreviations; ID, one-dimensional; 2D, two-dimensional; 6-AHA, 6-aminohexanoic acid; AcArgOMe, N"-acetyl-L-arginine methyl ester; AcLysOMe, N"-acetyl-L-lysine methyl ester; Acm, acetamidomethyl group; ADC, anti-distance constraints; CB-NTP, CNBr cleaved N-terminal peptide from human plasminogen, Glul-HSer57; CD, circular dichroism; COSY, 2D chemical shift correlated spectroscopy; DIEA, N,N-diisopropylethylamine; DMF, N,Ndimethylformamide; DSS, 3-(trimethylsilyl)-l-propanesulfonic acid, sodium salt; EM, energy minimization; Et20, anhydrous diethyl ether; FmoclrBu, 9-fluorenylmethyloxycarbonyl/terf-butyl; HATU, N-[(dimethylamino) (lH-1,2,3-triazolo[4,5-b]pyridin-I-yl) methylenel-N-methyl methanaminium hexafluorophosphate N-oxide; HOAt, 7-aza-I-hydroxy-benzotriazole; HOAc, glacial a...

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“…The conformational change of gluplasminogen can be mediated by small lysine analogues and α-enolase (Markus, 1996;Andronicos et al, 2000). Whilst the binding of glu-plasminogen to cells is low affinity (Felez, 1998;Ranson et al, 1998) this study demonstrated that binding may also stabilise an activation-susceptible conformation of glu-plasminogen on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…The low affinity of glu-plasminogen binding has led to suggestions that binding is not important for activation. However, the fact remains that gluplasminogen activation is enhanced in the presence of small lysine analogues, cells and proteins and that this is attributable to a more open conformation of glu-plasminogen (Markus, 1996).…”

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confidence: 99%

The topology of plasminogen binding and activation on the surface of human breast cancer cells

Andronicos

Ranson

2001

Br J Cancer

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SummaryThe urokinase-dependent activation of plasminogen by breast cancer cells plays an important role in metastasis. We have previously shown that the metastatic breast cancer cell line MDA-MB-231 over-expresses urokinase and binds and efficiently activates plasminogen at the cell surface compared to non-metastatic cells. The aim of this study was to further characterise plasminogen binding and determine the topology of cell surface-bound plasminogen in terms of its potential for activation. The lysine-dependent binding of plasminogen at 4˚C to MDA-MB-231 cells was stable and resulted in an activation-susceptible conformation of plasminogen. Topologically, a fraction of bound plasminogen was co-localised with urokinase on the surfaces of MDA-MB-231 cells where it could be activated to plasmin. At 37˚C plasmin was rapidly lost from the cell surface. Apart from actin, other candidate plasminogen receptors were either not expressed or did not co-localise with plasminogen at the cell surface. Thus, based on co-localisation with urokinase, plasminogen binding is partitioned into two functional pools on the surface of MDA-MB-231 cells. In conclusion, these results shed further light on the functional organisation of the plasminogen activation cascade on the surface of a metastatic cancer cell.

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Conformational changes in plasminogen, their effect on activation, and the agents that modulate activation rates — a review

Cited by 46 publications

References 73 publications

Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Structural/functional properties of the Glu1‐HSer57 N‐terminal fragment of human plasminogen: Conformational characterization and interaction with kringle domains

The topology of plasminogen binding and activation on the surface of human breast cancer cells

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