PDBsum entry: 2qja

Cytokine/receptor

PDB id: 2qja

Contents

Protein chains

104 a.a. *

85 a.a. *

93 a.a. *

Waters ×38

* Residue conservation analysis

PDB id:

2qja

Name:

Cytokine/receptor

Title:

Crystal structure analysis of bmp-2 in complex with bmpr-ia b12

Structure:

Bone morphogenetic protein 2. Chain: a, b. Fragment: mature part (residues 283-396). Synonym: bmp-2, bmp-2a. Engineered: yes. Bone morphogenetic protein receptor type ia. Chain: c, d. Fragment: extracellular domain (residues 24-152). Synonym: serine/threonine-protein kinase receptor r5, skr5,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bmp2, bmp2a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: bmpr1a, acvrlk3, alk3.

Resolution:

2.60Å R-factor: 0.216 R-free: 0.254

Authors:

A.Kotzsch,T.D.Mueller

Key ref:

A.Kotzsch et al. (2008). Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome. J Biol Chem, 283, 5876-5887. PubMed id: 18160401 DOI: 10.1074/jbc.M706029200

Date:

06-Jul-07 Release date: 15-Jan-08

Protein chains

P12643  (BMP2_HUMAN) -  Bone morphogenetic protein 2

Seq: 396 a.a.

Struc: 104 a.a.

Protein chain

P36894  (BMR1A_HUMAN) -  Bone morphogenetic protein receptor type-1A

Seq: 532 a.a.

Struc: 85 a.a.*

Protein chain

P36894  (BMR1A_HUMAN) -  Bone morphogenetic protein receptor type-1A

Seq: 532 a.a.

Struc: 93 a.a.*

* PDB and UniProt seqs differ at 22 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains C, D: E.C.2.7.11.30 - Receptor protein serine/threonine kinase.
• Reaction: ATP + [receptor-protein] = ADP + [receptor-protein] phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (2 terms)
• Biochemical function: growth factor activity (3 terms)

Added reference

DOI no: 10.1074/jbc.M706029200

J Biol Chem 283:5876-5887 (2008)

PubMed id: 18160401

Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.

A.Kotzsch, J.Nickel, A.Seher, K.Heinecke, L.van Geersdaele, T.Herrmann, W.Sebald, T.D.Mueller.

ABSTRACT

Bone morphogenetic proteins regulate many developmental processes during embryogenesis as well as tissue homeostasis in the adult. Signaling of bone morphogenetic proteins (BMPs) is accomplished by binding to two types of serine/threonine kinase transmembrane receptors termed type I and type II. Because a large number of ligands signal through a limited number of receptors, ligand-receptor interaction in the BMP superfamily is highly promiscuous, with a ligand binding to various receptors and a receptor binding many different BMP ligands. In this study we investigate the interaction of BMP-2 with its two high affinity type I receptors, BMP receptors IA (BMPR-IA) and BMPR-IB. Interestingly, 50% of the residues in the BMP-2 binding epitope of the BMPR-IA receptor are exchanged in BMPR-IB without a decrease in binding affinity or specificity for BMP-2. Our structural and functional analyses show that promiscuous binding of BMP-2 to both type I receptors is achieved by inherent backbone and side-chain flexibility as well as by variable hydration of the ligand-receptor interface enabling the BMP-2 surface to adapt to different receptor geometries. Despite the high degree of amino acid variability found in BMPR-IA and BMPR-IB binding equally to BMP-2, three single point missense mutations in the ectodomain of BMPR-IA cannot be tolerated. In juvenile polyposis syndrome these mutations have been shown to inactivate BMPR-IA. On the basis of our biochemical and biophysical analyses, we can show that the mutations, which are located outside the ligand binding epitope, alter the local or global fold of the receptor, thereby inactivating BMPR-IA and causing a loss of the BMP-2 tumor suppressor function in colon epithelial cells.

Selected figure(s)

Figure 4.
FIGURE 4. Two conformations exist for the BMPR-IA/IB^C binding loop 5. Superposition of the loop 1 of BMPR-IA marked in red (from the structure of BMP-2·BMPR-IA, pdb code 1REW) and BMPR-IA/IB^C (shown in dark and light blue) from both interfaces, with the closed conformational state (a) and the open conformation (b). The closed conformation in a closely resembles the loop conformation also observed for BMPR-IA in complex with BMP-2. c, open (light blue) and closed (dark blue) conformations of loop 5 superimposed onto each other (stereo image). In the open conformation the salt bridge between Asp-89 and Arg-97 is disrupted, and the side chain of Asp-89 swings out into the solvent, making an H-bond interaction with the backbone carbonyl of Ile-99.

Figure 5.
FIGURE 5. Mutations in the extracellular domain of BMPR-IA involved in JPS. a, three missense mutations in the extracellular domain of BMPR-IA are described as resulting in juvenile polyposis syndrome. The receptor BMPR-IA is shown as an orange surface presentation with the mutations highlighted in different colors. The bound BMP-2 is indicated as a magenta ribbon. Two of the mutations, P34R (yellow) and Y39D (blue), are located outside the BMP-2 binding epitope, having no contact with the bound ligand. The third mutation T55I (green) is close but in the periphery of the binding epitope. b, as in a but rotated 45° around the y axis. c, competition of BMP-2 activation of the BRE luciferase reporter by the addition of recombinant BMPR-IA ectodomain protein or variant proteins. d, rescue of BMP-2-mediated inhibition of proliferation of MPC11 cells. The addition of 5 nM BMP-2 reduces the proliferation to 50%; recombinant BMPR-IA proteins (wild type or variant) were added to determine competition efficiencies. e-g, magnification of the BMPR-IA region around the three residues affected in JPS: Y39D (e), T55I (f), and P34R (g). Residues are represented by sticks and colored by protein identity (BMPR-IA: cyan, C; blue, N; red, O; BMP-2: green, C). Residues P34R, Y39D, and T55I are shown in yellow, and hydrogen bonds are shown as dashed lines.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 5876-5887) copyright 2008.

Figures were selected by the author.