Mutational Analysis of Affinity and Selectivity of Kringle-Tetranectin Interaction

Graversen, Jonas Heilskov; Jacobsen, Christian; Sigurskjold, Bent W.; Lorentsen, Rikke Høegh; Moestrup, Søren K.; Thøgersen, Henning; Etzerodt, Michael

doi:10.1074/jbc.m004873200

Cited by 11 publications

(2 citation statements)

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“…Some plasminogen binding molecules interact with a single LBS of plasminogen through multiple residues ( e.g ., at least one amino acid with a negatively charged side chain and one with a positively charged side chain) that mimic the charge properties of AHA. For example, three charged residues of tetranectin (Lys148, Glu150, and Asp165) are involved in its interaction with kringle 4 of plasminogen (54). Similarly, the LBS of plasminogen kringle 2 interacts electrostatically with Arg17, His18, Asp54, and Asp56 of the Group A streptococcal M-like protein (PAM), VEK-30 (55).…”

Section: Discussionmentioning

confidence: 99%

Residues Essential for Plasminogen Binding by the Cation-Independent Mannose 6-Phosphate Receptor

et al. 2009

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The 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR) is a multifunctional protein that binds diverse intracellular and extracellular ligands with high affinity. The CI-MPR is a receptor for plasminogen and this interaction can be inhibited by lysine analogues. To characterize the molecular basis for this interaction, surface plasmon resonance (SPR) analyses were performed using truncated forms of the CI-MPR and plasminogen. The results show that the N-terminal region of the CI-MPR containing domains 1 and 2, but not domain 1 alone, of the receptor's 15-domain extracytoplasmic region binds plasminogen (K d = 5 ± 1 nM) with an affinity similar to that of the full-length receptor (K d = 20 ± 6 nM). In addition to its C-terminal serine protease domain, plasminogen contains lysine binding sites (LBS), which are located within each of its five kringle domains, except kringle 3. We show that kringles 1-4, but not kringles 1-3, bind the CI-MPR, indicating an essential role for the LBS in kringle 4 of plasminogen. To identify the lysine residue (s) of the CI-MPR that serves as an essential determinant for recognition by the LBS of plasminogen, site-directed mutagenesis studies were carried out using a construct encoding the N-terminal three domains of the CI-MPR (Dom1-3His) which contains both a mannose 6-phosphate (Man-6-P) and plasminogen binding site. The results demonstrate two lysine residues (Lys 53 located in domain 1 and Lys125 located in the loop connecting domains 1 and 2) of the CI-MPR are key determinants for plasminogen binding, but are not required for Man-6-P binding.Plasminogen, the precursor of the serine protease plasmin and the anti-angiogenic molecules, the angiostatins, is synthesized by liver and extrahepatic cells as a 92 kDa glycoprotein. It is a key component of the plasminogen activation system that is important in fibrinolysis, cell migration, tissue remodeling, inflammation, and tumor cell invasion. Glu-plasminogen, the full-length form of plasminogen, consists of seven domains: an N-terminal PAN (plasminogen/ Apple/Nematode) module, five kringle domains (K1-K5), and a C-terminal serine protease domain with trypsin-like activity (1,2). The kringle domains, each ~80 residues in length, share a common double-loop disulfide structure and are responsible for plasminogen binding to extracellular matrix proteins by the lysine binding site (LBS) 1 found in some (K1, K2, K4, and K5, with K2 and K5 exhibiting the weakest binding), but not all (K3), of the kringle domains † This work was supported in part by National Institutes of Health Grants R01DK42667 (to N.M.D.) and R01EY012731 (to S.S.T.) *Address correspondence to: Nancy M. Dahms, Ph.D., Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee,, ndahms@mcw.edu. SUPPORTING INFORMATION A supplemental figure showing the secondary structure and oligomeric state of Dom1His can be accessed free of charge at http://pubs.acs.org. 1 The abbreviations used are: Glu-plasminogen, full-length plas...

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Section: Discussionmentioning

confidence: 99%

Residues Essential for Plasminogen Binding by the Cation-Independent Mannose 6-Phosphate Receptor

et al. 2009

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“…33 When pre-incubated with the lysine analogue 6-AHA, the SPR analysis showed inhibition of FH binding to α-FXIIa, demonstrating that FH likely binds the kringle domain on the heavy chain of α-FXIIa. However, the interaction was much less sensitive than observed for other kringle-protein interactions, 34 probably reflecting that the lysine binding site is only semi-conserved, and therefore…”

Section: Discussionmentioning

confidence: 71%

Contact activation‐induced complex formation between complement factor H and coagulation factor XIIa

Thangaraj

Christiansen

Graversen

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The complement and coagulation systems share an evolutionary origin with many components showing structural homology. Certain components, including complement factor H (FH) and coagulation factor XII (FXII), have separately been shown to have auxiliary activities across the two systems. Objectives The interaction between FXII and FH was investigated. Methods Using enzyme‐linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) complex formation between different FXII forms and FH was investigated. The presence of α‐FXIIa:FH complexes upon contact activation in plasma was evaluated by ELISA and immunoprecipitation. Results We identified and characterized a direct interaction between the components and demonstrated that among different forms of FXII, only the activated α‐FXIIa formed complexes with FH, with an apparent binding strength Kd of 34 ± 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1‐inhibitor induced inhibition of α‐FXIIa did not alter the binding of α‐FXIIa toward FH. We further demonstrated the presence of α‐FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of α‐FXIIa:FH complexes as a consequence of α‐FXIIa generation. Complex formation between α‐FXIIa and FH was also assessed in hereditary angioedema (HAE) patients with C1‐inhibitor deficiency as well as rheumatoid arthritis (RA) patients with high levels of anti‐cyclic citrullinated peptide (anti‐CCP) upon contact activation. We observed elevated levels of α‐FXIIa:FH complexes in HAE patients, and equal levels of complexes in RA patients and healthy individuals upon contact activation. Conclusion A direct interaction between α‐FXIIa and FH is demonstrated. Our findings represent a new crosstalk between these systems, potentially important in the onset and pathology of inflammatory vascular diseases.

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Survey of the year 2000 commercial optical biosensor literature

Rich

Myszka

2001

J of Molecular Recognition

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We have compiled a comprehensive list of the articles published in the year 2000 that describe work employing commercial optical biosensors. Selected reviews of interest for the general biosensor user are highlighted. Emerging applications in areas of drug discovery, clinical support, food and environment monitoring, and cell membrane biology are emphasized. In addition, the experimental design and data processing steps necessary to achieve high-quality biosensor data are described and examples of well-performed kinetic analysis are provided.

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Mutational Analysis of Affinity and Selectivity of Kringle-Tetranectin Interaction

Cited by 11 publications

References 38 publications

Residues Essential for Plasminogen Binding by the Cation-Independent Mannose 6-Phosphate Receptor

Residues Essential for Plasminogen Binding by the Cation-Independent Mannose 6-Phosphate Receptor

Contact activation‐induced complex formation between complement factor H and coagulation factor XIIa

Survey of the year 2000 commercial optical biosensor literature

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