PDBsum entry: 2pjy

Cytokine/cytokine receptor

PDB id: 2pjy

Contents

Protein chains

112 a.a. *

108 a.a. *

79 a.a. *

Waters ×9

* Residue conservation analysis

PDB id:

2pjy

Name:

Cytokine/cytokine receptor

Title:

Structural basis for cooperative assembly of the tgf-beta si complex

Structure:

Transforming growth factor beta-3. Chain: a. Synonym: tgf-beta-3. Engineered: yes. Tgf-beta receptor type-2. Chain: b. Fragment: extracellular domain. Synonym: tgf-beta receptor type ii, tgfr-2, tgf-beta type i receptor, transforming growth factor-beta receptor type ii,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tgfb3. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: tgfbr2. Gene: tgfbr1. Expression_system_taxid: 562

Resolution:

3.00Å R-factor: 0.244 R-free: 0.297

Authors:

J.Groppe,C.Zubieta

Key ref:

J.Groppe et al. (2008). Cooperative assembly of tgf-Beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell, 29, 157-168. PubMed id: 18243111 DOI: 10.1016/j.molcel.2007.11.039

Date:

16-Apr-07 Release date: 05-Feb-08

Protein chain

P10600  (TGFB3_HUMAN) -  Transforming growth factor beta-3

Seq: 412 a.a.

Struc: 112 a.a.

Protein chain

P37173  (TGFR2_HUMAN) -  TGF-beta receptor type-2

Seq: 567 a.a.

Struc: 108 a.a.*

Protein chain

P36897  (TGFR1_HUMAN) -  TGF-beta receptor type-1

Seq: 503 a.a.

Struc: 79 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains B, C: 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: membrane (3 terms)
• Biological process: cell growth (3 terms)
• Biochemical function: receptor activity (9 terms)

Added reference

DOI no: 10.1016/j.molcel.2007.11.039

Mol Cell 29:157-168 (2008)

PubMed id: 18243111

Cooperative assembly of tgf-Beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.

J.Groppe, C.S.Hinck, P.Samavarchi-Tehrani, C.Zubieta, J.P.Schuermann, A.B.Taylor, P.M.Schwarz, J.L.Wrana, A.P.Hinck.

ABSTRACT

Dimeric ligands of the transforming growth factor-beta (TGF-beta) superfamily signal across cell membranes in a distinctive manner by assembling heterotetrameric complexes of structurally related serine/threonine-kinase receptor pairs. Unlike complexes of the bone morphogenetic protein (BMP) branch that apparently form due to avidity from membrane localization, TGF-beta complexes assemble cooperatively through recruitment of the low-affinity (type I) receptor by the ligand-bound high-affinity (type II) pair. Here we report the crystal structure of TGF-beta3 in complex with the extracellular domains of both pairs of receptors, revealing that the type I docks and becomes tethered via unique extensions at a composite ligand-type II interface. Disrupting the receptor-receptor interactions conferred by these extensions abolishes assembly of the signaling complex and signal transduction (Smad activation). Although structurally similar, BMP and TGF-beta receptors bind in dramatically different modes, mediating graded and switch-like assembly mechanisms that may have coevolved with branch-specific groups of cytoplasmic effectors.

Selected figure(s)

Figure 4.
Figure 4. TβRI Binds in a Distinct Mode at a Composite Interface
(A) Superposition of TGF-β3[A] onto BMP-2[A] (gold) in the BMP-2:BMPRIA binary complex. The surface of BMPRIA is represented in gray (TGF-β3[B], BMP-2[B] not depicted for simplicity).
(B) Superposition of the BMP binary and TGF-β ternary complexes. TβRI is rotated vert, similar 45° around the long axis of the ligand relative to BMPRIA. TGF-β3[A] and TGF-β3[B] are shown as red and blue surfaces, respectively (TβRII and BMP-2 not depicted).
(C) TGF-β3[A] and TβRI are separated by a wide solvent-filled channel. Molecular surfaces are depicted over the ribbons of TGF-β3[A] and TβRI (yellow-gold).
(D) Prehelix extension of TβRI binds long finger of ligand monomer. Prehelix extension highlighted in red, and ligand monomers are colored and oriented as in the figure above (TβRII not depicted).
(E) TβRI Arg58-TβRII Asp118 ion pair at the composite interface. TβRII is shown as ribbon in green, and ligand monomers and TβRI are as above.
(F) TβRII N-terminal extension tethers TβRI to the composite TGFβ3-TβRII interface. The seven ordered residues (Asn19–Pro25) of the N-terminal extension of TβRII (green) are shown as sticks. TβRI (yellow-gold) is depicted as sticks and as surface. In total, vert, similar 916 Å^2 of TβRI surface is buried upon binding by TβRII.

Figure 5.
Figure 5. N-Terminal Tether of TβRII Recruits TβRI into Ternary Complex
(A) Sequence of N-terminal extension of TβRII. The N-terminal tether (underlined, light green) extends out from the receptor scaffold (dark green) from Pro25 to Asn19. The first 18 residues appear to be unstructured. Numbering (based on the mature N terminus, not the initiator methionine of the signal peptide) refers to the termini of the receptor constructs below.
(B) Native gel analyses of TβRI recruitment by binary complexes of TGFβ3 and N-terminally truncated TβRII variants. BC and TC indicate positions of binary and ternary complexes, respectively.
(C) Native gel analyses of TβRI recruitment by binary complexes of TGF-β3 and Δ20 TβRII point variants.
(D) SPR analyses of TβRI recruitment by binary complexes of Δ20 TβRII point variants and fully truncated (Δ25) TβRII.

The above figures are reprinted by permission from Cell Press: Mol Cell (2008, 29, 157-168) copyright 2008.

Figures were selected by the author.