PDBsum entry 1mkn

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Heparin-binding growth factor PDB id
Protein chain
59 a.a. *
* Residue conservation analysis
PDB id:
Name: Heparin-binding growth factor
Title: N-terminal half of midkine
Structure: Protein (midkine). Chain: a. Fragment: n-terminal half. Engineered: yes
Source: Synthetic: yes. Other_details: the protein was chemically synthesized. The sequence of this protein is naturally found in homo sapiens (human).
NMR struc: 1 models
Authors: W.Iwasaki,K.Nagata,H.Hatanaka,K.Ogura,T.Inui,T.Kimura, T.Muramatsu,K.Yoshida,M.Tasumi,F.Inagaki
Key ref:
W.Iwasaki et al. (1997). Solution structure of midkine, a new heparin-binding growth factor. EMBO J, 16, 6936-6946. PubMed id: 9384573 DOI: 10.1093/emboj/16.23.6936
16-Mar-99     Release date:   23-Mar-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P21741  (MK_HUMAN) -  Midkine
143 a.a.
59 a.a.
Key:    PfamA domain  Secondary structure  CATH domain


DOI no: 10.1093/emboj/16.23.6936 EMBO J 16:6936-6946 (1997)
PubMed id: 9384573  
Solution structure of midkine, a new heparin-binding growth factor.
W.Iwasaki, K.Nagata, H.Hatanaka, T.Inui, T.Kimura, T.Muramatsu, K.Yoshida, M.Tasumi, F.Inagaki.
Midkine (MK) is a 13 kDa heparin-binding polypeptide which enhances neurite outgrowth, neuronal cell survival and plasminogen activator activity. MK is structurally divided into two domains, and most of the biological activities are located on the C-terminal domain. The solution structures of the two domains were determined by NMR. Both domains consist of three antiparallel beta-strands, but the C-terminal domain has a long flexible hairpin loop where a heparin-binding consensus sequence is located. Basic residues on the beta-sheet of the C-terminal domain form another heparin-binding site. Measurement of NMR signals in the presence of a heparin oligosaccharides verified that multiple amino acids in the two sites participated in heparin binding. The MK dimer has been shown to be the active form, giving signals to endothelial cells and probably to neuronal cells. We present a head-to-head dimer model of MK. The model was supported by the results of cross-linking experiments using transglutaminase. The dimer has a fused heparin-binding site at the dimer interface of the C-terminal domain, and the heparin-binding sites on MK fit the sulfate group clusters on heparin. These features are consistent with the proposed stronger heparin-binding activity and biological activity of the dimer.
  Selected figure(s)  
Figure 5.
Figure 5 Number of inter-residue NOE constraints and r.m.s.d.s for each residue of (A) MK(1 -59) and (B) MK(62 -104). The number of sequential distance constraints (gray bars), medium-range distance constraints with 2 |i -j|
Figure 10.
Figure 10 The model for binding of MK(62 -104) dimer on the heparin 20mer units with two conformations. (A) The model for heparin and MK(62 -104) head-to-head dimer complex (blue, basic residues; red, acidic residues; green, Gln; and pink, oxygens of sulfate groups). Positively charged clusters (blue dotted circles) of MK(62 -104) fit to negatively charged clusters (pink dotted circles) of heparin. (B) The opposite surface of MK(62 -104) to that shown in (A). The acidic residues of MK(62 -104) are localized opposite the heparin-binding surface. Gln95 which is attacked by transglutaminase is exposed opposite to the heparin-binding surface and is in close proximity to Lys63 on the counterpart. Lys63 is thought to be an amine donor in the transglutaminase reaction. (C) Side view of (A). The sulfate groups are localized on the right and left sides of the heparin molecule. Basic charged clusters in MK(62 -104) dimer fit the clusters of sulfate groups.
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1997, 16, 6936-6946) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21223602 H.Muramatsu1, K.Yokoi, L.Chen, K.Ichihara-Tanaka, T.Kimura, and T.Muramatsu (2011).
Midkine as a factor to counteract the deposition of amyloid β-peptide plaques: in vitro analysis and examination in knockout mice.
  Int Arch Med, 4, 1.  
20208353 K.Nagata (2010).
Studies of the structure-activity relationships of peptides and proteins involved in growth and development based on their three-dimensional structures.
  Biosci Biotechnol Biochem, 74, 462-470.  
20565917 T.Matsui, K.Ichihara-Tanaka, C.Lan, H.Muramatsu, T.Kondou, C.Hirose, S.Sakuma, and T.Muramatsu (2010).
Midkine inhibitors: application of a simple assay procedure to screening of inhibitory compounds.
  Int Arch Med, 3, 12.  
20431264 T.Muramatsu (2010).
Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases.
  Proc Jpn Acad Ser B Phys Biol Sci, 86, 410-425.  
19263476 A.A.Calinescu, T.S.Vihtelic, D.R.Hyde, and P.F.Hitchcock (2009).
Cellular expression of midkine-a and midkine-b during retinal development and photoreceptor regeneration in zebrafish.
  J Comp Neurol, 514, 1.  
  19235265 Z.H.Zhang, L.J.Du, D.Xiang, S.Y.Zhu, M.Y.Wu, H.L.Lu, Y.Yu, and W.Han (2009).
Expression and purification of bioactive high-purity human midkine in Escherichia coli.
  J Zhejiang Univ Sci B, 10, 79-86.  
18195496 Y.Yoshida, S.Ikematsu, H.Muramatsu, H.Sakakima, N.Mizuma, F.Matsuda, K.Sonoda, F.Umehara, R.Ohkubo, E.Matsuura, M.Goto, M.Osame, and T.Muramatsu (2008).
Expression of the heparin-binding growth factor midkine in the cerebrospinal fluid of patients with neurological disorders.
  Intern Med, 47, 83-89.  
17066487 N.Akuzawa, S.Nobata, and T.Shinozawa (2007).
Truncated midkine correlates with sensitivity to anticancer drugs and malignancy in human tumor cell line.
  Cell Biochem Funct, 25, 687-691.  
16220264 C.Englund, A.Birve, L.Falileeva, C.Grabbe, and R.H.Palmer (2006).
Miple1 and miple2 encode a family of MK/PTN homologues in Drosophila melanogaster.
  Dev Genes Evol, 216, 10-18.  
16373346 N.Maeda, N.Fukazawa, and T.Hata (2006).
The binding of chondroitin sulfate to pleiotrophin/heparin-binding growth-associated molecule is regulated by chain length and oversulfated structures.
  J Biol Chem, 281, 4894-4902.  
16619002 P.Zou, H.Muramatsu, M.Sone, H.Hayashi, T.Nakashima, and T.Muramatsu (2006).
Mice doubly deficient in the midkine and pleiotrophin genes exhibit deficits in the expression of beta-tectorin gene and in auditory response.
  Lab Invest, 86, 645-653.  
16156786 E.A.Said, J.Courty, J.Svab, J.Delbé, B.Krust, and A.G.Hovanessian (2005).
Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin.
  FEBS J, 272, 4646-4659.  
16155004 E.Raulo, S.Tumova, I.Pavlov, M.Pekkanen, A.Hienola, E.Klankki, N.Kalkkinen, T.Taira, I.Kilpelaïnen, and H.Rauvala (2005).
The two thrombospondin type I repeat domains of the heparin-binding growth-associated molecule bind to heparin/heparan sulfate and regulate neurite extension and plasticity in hippocampal neurons.
  J Biol Chem, 280, 41576-41583.  
15054901 I.Pavlov, S.Lauri, T.Taira, and H.Rauvala (2004).
The role of ECM molecules in activity-dependent synaptic development and plasticity.
  Birth Defects Res C Embryo Today, 72, 12-24.  
14970216 N.Suzuki, Y.Shibata, T.Urano, T.Murohara, T.Muramatsu, and K.Kadomatsu (2004).
Proteasomal degradation of the nuclear targeting growth factor midkine.
  J Biol Chem, 279, 17785-17791.  
12743018 C.Winkler, M.Schafer, J.Duschl, M.Schartl, and J.N.Volff (2003).
Functional divergence of two zebrafish midkine growth factors following fish-specific gene duplication.
  Genome Res, 13, 1067-1081.  
12147681 E.A.Said, B.Krust, S.Nisole, J.Svab, J.P.Briand, and A.G.Hovanessian (2002).
The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin as a low affinity receptor.
  J Biol Chem, 277, 37492-37502.  
12391027 K.Tan, M.Duquette, J.H.Liu, Y.Dong, R.Zhang, A.Joachimiak, J.Lawler, and J.H.Wang (2002).
Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication.
  J Cell Biol, 159, 373-382.
PDB code: 1lsl
12421346 R.Mentlein, and J.Held-Feindt (2002).
Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas.
  J Neurochem, 83, 747-753.  
11959856 Y.Takei, K.Kadomatsu, H.Itoh, W.Sato, K.Nakazawa, S.Kubota, and T.Muramatsu (2002).
5'-,3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy.
  J Biol Chem, 277, 23800-23806.  
11758924 A.Murasugi, and Y.Tohma-Aiba (2001).
Comparison of three signals for secretory expression of recombinant human midkine in Pichia pastoris.
  Biosci Biotechnol Biochem, 65, 2291-2293.  
11598131 L.Desnoyers, D.Arnott, and D.Pennica (2001).
WISP-1 binds to decorin and biglycan.
  J Biol Chem, 276, 47599-47607.  
11245814 Y.Yoshida, S.Ikematsu, T.Moritoyo, M.Goto, J.Tsutsui, S.Sakuma, M.Osame, and T.Muramatsu (2001).
Intraventricular administration of the neurotrophic factor midkine ameliorates hippocampal delayed neuronal death following transient forebrain ischemia in gerbils.
  Brain Res, 894, 46-55.  
  16232878 A.Murasugi, Y.Tohma-Aiba, and Y.Asami (2000).
Production of recombinant human midkine in yeast, Pichia pastoris.
  J Biosci Bioeng, 90, 395-399.  
10788472 I.Kilpelainen, M.Kaksonen, T.Kinnunen, H.Avikainen, M.Fath, R.J.Linhardt, E.Raulo, and H.Rauvala (2000).
Heparin-binding growth-associated molecule contains two heparin-binding beta -sheet domains that are homologous to the thrombospondin type I repeat.
  J Biol Chem, 275, 13564-13570.  
11029577 J.McLaurin, and P.E.Fraser (2000).
Effect of amino-acid substitutions on Alzheimer's amyloid-beta peptide-glycosaminoglycan interactions.
  Eur J Biochem, 267, 6353-6361.  
10866805 K.Zou, H.Muramatsu, S.Ikematsu, S.Sakuma, R.H.Salama, T.Shinomura, K.Kimata, and T.Muramatsu (2000).
A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican.
  Eur J Biochem, 267, 4046-4053.  
10821669 L.Qiu, C.R.Escalante, A.K.Aggarwal, P.D.Wilson, and C.R.Burrow (2000).
Monomeric midkine induces tumor cell proliferation in the absence of cell-surface proteoglycan binding.
  Biochemistry, 39, 5977-5987.  
10683378 M.Horiba, K.Kadomatsu, E.Nakamura, H.Muramatsu, S.Ikematsu, S.Sakuma, K.Hayashi, Y.Yuzawa, S.Matsuo, M.Kuzuya, T.Kaname, M.Hirai, H.Saito, and T.Muramatsu (2000).
Neointima formation in a restenosis model is suppressed in midkine-deficient mice.
  J Clin Invest, 105, 489-495.  
10748319 M.Lesort, J.Tucholski, M.L.Miller, and G.V.Johnson (2000).
Tissue transglutaminase: a possible role in neurodegenerative diseases.
  Prog Neurobiol, 61, 439-463.  
10632704 N.Kurosawa, K.Kadomatsu, S.Ikematsu, S.Sakuma, T.Kimura, and T.Muramatsu (2000).
Midkine binds specifically to sulfatide the role of sulfatide in cell attachment to midkine-coated surfaces.
  Eur J Biochem, 267, 344-351.  
10954861 S.Ikeda, A.Nishikimi, K.Ichihara-Tanaka, T.Muramatsu, and M.Yamada (2000).
cDNA cloning of bovine midkine and production of the recombinant protein, which affects in vitro maturation of bovine oocytes.
  Mol Reprod Dev, 57, 99.  
10336660 C.H.Chau, D.K.Shum, Y.S.Chan, and K.F.So (1999).
Heparan sulphates upregulate regeneration of transected sciatic nerves of adult guinea-pigs.
  Eur J Neurosci, 11, 1914-1926.  
10497173 M.Rusnati, G.Tulipano, D.Spillmann, E.Tanghetti, P.Oreste, G.Zoppetti, M.Giacca, and M.Presta (1999).
Multiple interactions of HIV-I Tat protein with size-defined heparin oligosaccharides.
  J Biol Chem, 274, 28198-28205.  
10208385 N.Iwashita, H.Muramatsu, K.Toriyama, S.Torii, and T.Muramatsu (1999).
Expression of midkine in normal and burn sites of rat skin.
  Burns, 25, 119-124.  
10212223 N.Maeda, K.Ichihara-Tanaka, T.Kimura, K.Kadomatsu, T.Muramatsu, and M.Noda (1999).
A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a heparin-binding growth factor midkine. Involvement of arginine 78 of midkine in the high affinity binding to PTPzeta.
  J Biol Chem, 274, 12474-12479.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.