PDBsum entry 1mkc

Heparin-binding growth factor

PDB id: 1mkc

Contents

Protein chain

43 a.a. *

* Residue conservation analysis

PDB id:

1mkc

Name:

Heparin-binding growth factor

Title:

C-terminal domain of midkine

Structure:

Protein (midkine). Chain: a. Fragment: c-terminal domain. 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

Date:

16-Mar-99 Release date: 23-Mar-99

Protein chain

P21741  (MK_HUMAN) -  Midkine from Homo sapiens

Seq: 143 a.a.

Struc: 43 a.a.

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.

ABSTRACT

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.