Kringle‐kringle interactions in multimer kringle structures

Padmanabhan, K.; Wu, Tswei Ping; Ravichandran, K. G.; Tulinsky, A.

doi:10.1002/pro.5560030605

Cited by 17 publications

(15 citation statements)

References 49 publications

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“…An HGF dimer, formed by noncovalent interactions between kringles 2 and 3 of the protein pair, has been suggested as the moiety that induces dimerization and activation of MET (29). This idea is supported by a report of nonconvalent kringle-kringle interactions (32). Although MSP and HGF have different primary receptor binding regions, they may have a similar structural basis for receptor activation by dimer formation through kringle interactions.…”

Section: Effect Of Msp Subunits On Msp-induced Cell Shapesupporting

confidence: 59%

Macrophage Stimulating Protein (MSP) Binds to Its Receptor via the MSP β Chain

Wang¹,

Julian²,

Breathnach³

et al. 1997

Journal of Biological Chemistry

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Macrophage stimulating protein (MSP)1 was originally purified from human plasma, based on its activity for murine resident peritoneal macrophages (1). It is a 78-kDa heterodimeric protein composed of a disulfide-linked 53-kDa ␣ chain and a 25-kDa ␤ chain (calculated from amino acid composition). The ␣ chain contains a N-terminal hairpin loop followed by four kringle domains. The ␤ chain has a serine protease-like domain but is devoid of enzymatic activity due to amino acid substitutions in the catalytic triad. MSP belongs to the kringle protein family that includes plasminogen (2) and hepatocyte growth factor/scatter factor (HGF/SF) (3, 4). MSP is synthesized mainly by liver cells (5, 6), circulates in blood as a biologically inactive single chain precursor (7), and is cleaved by members of the kallikrein family (8, 9) or by trypsin-like enzymes located on macrophage surfaces (7). Recent functional studies have revealed that in addition to induction of macrophage shape change, chemotactic migration (10), and phagocytosis of C3bi-coated erythrocytes (1), MSP has other activities. These include inhibition of expression of inducible nitric oxide synthase mRNA in endotoxin or cytokine-stimulated macrophages (11), induction of interleukin-6 production and differentiation of megakaryocytes (12), suppression of colony formation of human bone marrow cells induced by Steel factor plus granulocyte macrophage-stimulating factor (13), increase in beat frequency of nasal epithelium cilia (14), and stimulation in vitro of proliferation of certain epithelial cell lines (15-17).The receptor for MSP was recently identified as the human RON gene product (18), a transmembrane receptor proteintyrosine kinase cloned from a human keratinocyte cDNA library (19). The murine STK gene cloned from hematopoietic stem cells of bone marrow is the homologue of human RON (20,21). The RON gene encodes a 190-kDa heterodimeric protein composed of a 40-kDa extracellular ␣ chain and 150-kDa transmembrane ␤ chain with intrinsic tyrosine kinase activity (21). This property places the product of the RON/STK gene into a subfamily of receptor tyrosine kinases that includes proto-oncogene MET and SEA (22,23). These receptors share many unique structural properties including a putative proteolytic cleavage site, similar location of cysteine residues in their extracellular domain, and two conserved tyrosines in the Cterminal tail (19,20,22,23). Studies of the signaling pathways of RON have shown that tyrosine-phosphorylated RON associates in vivo with intracellular signal transducers, including Grb-2-Sos and phosphatidylinositol 3-kinase (17, 24).In this work, we initiated a structure-activity study of MSP to identify functionally important domains that interact with the RON receptor. Five purified recombinant proteins were used, including pro-MSP, MSP, MSP ␣ and ␤ chains, and the MSP N terminus (including the first two kringles) fused to human IgG Fc. We report the binding capacity of MSP and its subunits to RON receptor in intact cells. We also analyzed ...

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Section: Effect Of Msp Subunits On Msp-induced Cell Shapesupporting

confidence: 59%

Macrophage Stimulating Protein (MSP) Binds to Its Receptor via the MSP β Chain

Wang¹,

Julian²,

Breathnach³

et al. 1997

Journal of Biological Chemistry

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“…Kringle 2 of molecule 1 could then accommodate a lysine residue from kringle 3 of molecule 2 (it could be either Lys,, or Lys,, , the only 2 Lys residues in the sequence of kringle 3) into its putative lysine-binding pocket and, vice versa, kringle 2 of molecule 2 could interact with a Lys residue from kringle 3 of molecule 1. This type of ligand-like binding interaction between kringles has been recently reported in t-PA kringle 2 crystals (Padmanabhan et al, 1994). The putative noncovalent HGF/SF homodimer might also be held through direct interactions between the serine proteinase domains of each molecule mediated by the catalytic cleft and/or the S1 pocket; this could accommodate residues, other than arginine, from the serine proteinase domain of one of the HGF/SF molecules.…”

Section: E Q H K M R M V L G V I V P G R --G C a I P N R P G I F V R supporting

confidence: 58%

Molecular evolution and domain structure of plasminogen‐related growth factors (HGF/SF and HGF1/MSP)

et al. 1994

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Plasminogen-related growth factors, a new family of polypeptide growth factors with the basic domain organization and mechanism of activation of the blood proteinase plasminogen, include hepatocyte growth factorhcatter factor (HGF/SF), a potent effector of the growth, movement, and differentiation of epithelia and endothelia, and hepatocyte growth factor-like/macrophage stimulating protein (HGFVMSP), an effector of macrophage chemotaxis and phagocytosis. Phylogeny of the serine proteinase domains and analysis of intron-exon boundaries and kringle sequences indicate that HGF/SF, HGFVMSP, plasminogen, and apolipoprotein (a) have evolved from a common ancestral gene that consisted of an N-terminal domain corresponding to plasminogen activation peptide (PAP), 3 copies of the kringle domain, and a serine proteinase domain. Models of the N domains of HGF/SF, HGFVMSP, and plasminogen, characterized by the presence of 4 conserved Cys residues forming a loop in a loop, have been modeled based on disulfide-bond constraints. There is a distinct pattern of charged and hydrophobic residues in the helix-strand-helix motif proposed for the PAP domain of HGF/SF; these may be important for receptor interaction. Three-dimensional structures of the 4 kringle and the serine proteinase domains of HGF/SF were constructed by comparative modeling using the suite of programs COMPOSER and were energy minimized. Docking of a lysine analogue indicates a putative lysine-binding pocket within kringle 2 (and possibly another in kringle 4). The models suggest a mechanism for the formation of a noncovalent HGF/SF homodimer that may be responsible for the activation of the Met receptor. These data provide evidence for the divergent evolution and structural similarity of plasminogen, HGF/SF, and HGFVMSP, and highlight a new strategy for growth factor evolution, namely the adaptation of a proteolytic enzyme to a role in receptor activation.Keywords: HGF/SF; HGFVMSP; kringle; Met receptor; plasminogen-related growth factors; serine proteinase Polypeptide growth factors are a diverse group of proteins that regulate the growth, movement, and differentiation of higher eukaryotic cells and exert their activity through specific membrane receptors that transduce the growth factor signal (Ullrich

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“…Kringles are small structural elements (i.e., 60 amino acids) found in hundreds of proteins in the genome and usually mediate protein-protein interactions ( 18 ). In agreement with this knowledge, previous studies have proposed interactions between kringle-1 and kringle-2 with fVa and fXa during the assembly of the prothrombinase complex ( 19 , 20 ).…”

Section: Prothrombin Gene and Domain Organizationmentioning

confidence: 99%

Structure of Coagulation Factor II: Molecular Mechanism of Thrombin Generation and Development of Next-Generation Anticoagulants

2018

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Coagulation factor II, or prothrombin, is a multi-domain glycoprotein that is essential for life and a key target of anticoagulant therapy. In plasma, prothrombin circulates in two forms at equilibrium, “closed” (~80%) and “open” (~20%), brokered by the flexibility of the linker regions. Its structure remained elusive until recently when our laboratory solved the first X-ray crystal structure of the zymogen locked in the predominant closed form. Because of this technical breakthrough, fascinating aspects of the biology of prothrombin have started to become apparent, and with this, novel and important questions arise. Here, we examine the significance of the “closed”/“open” equilibrium in the context of the mechanism of thrombin generation. Further, we discuss the potential translational opportunities for the development of next-generation anticoagulants that arise from this discovery. By providing a structural overview of each alternative conformation, this minireview also offers a relevant example of modern structural biology and establishes a practical workflow to elucidate the structural features of analogous clotting and complement factors.

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Kringle‐kringle interactions in multimer kringle structures

Cited by 17 publications

References 49 publications

Macrophage Stimulating Protein (MSP) Binds to Its Receptor via the MSP β Chain

Macrophage Stimulating Protein (MSP) Binds to Its Receptor via the MSP β Chain

Molecular evolution and domain structure of plasminogen‐related growth factors (HGF/SF and HGF1/MSP)

Structure of Coagulation Factor II: Molecular Mechanism of Thrombin Generation and Development of Next-Generation Anticoagulants

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