PDBsum entry: 2izv

Transcription

PDB id: 2izv

Contents

Protein chains

163 a.a. *

105 a.a. *

85 a.a. *

Ligands

EDO

Metals

_CL

_NA

Waters ×113

* Residue conservation analysis

PDB id:

2izv

Name:

Transcription

Title:

Crystal structure of socs-4 in complex with elongin-b and elongin-c at 2.55a resolution

Structure:

Suppressor of cytokine signaling 4. Chain: a. Fragment: residues 274-437. Synonym: socs-4 elongin b, c complex, socs-4, socs-7, suppr cytokine signaling 7. Engineered: yes. Transcription elongation factor b polypeptide 2. Chain: b. Synonym: RNA polymerase ii transcription factor siii subuni

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: bl21(de3)-r3.

Biol. unit:

Trimer (from PDB file)

Resolution:

2.55Å R-factor: 0.175 R-free: 0.223

Authors:

J.E.Debreczeni,A.Bullock,E.Papagrigoriou,A.Turnbull,A.C.W.Pi F.Gorrec,F.Von Delft,M.Sundstrom,C.Arrowsmith,J.Weigelt,A.E S.Knapp

Key ref:

A.N.Bullock et al. (2007). Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. Structure, 15, 1493-1504. PubMed id: 17997974 DOI: 10.1016/j.str.2007.09.016

Date:

26-Jul-06 Release date: 02-Aug-06

Protein chain

Q8WXH5  (SOCS4_HUMAN) -  Suppressor of cytokine signaling 4

Seq: 440 a.a.

Struc: 163 a.a.*

Protein chain

Q15370  (ELOB_HUMAN) -  Transcription elongation factor B polypeptide 2

Seq: 118 a.a.

Struc: 105 a.a.

Protein chain

Q15369  (ELOC_HUMAN) -  Transcription elongation factor B polypeptide 1

Seq: 112 a.a.

Struc: 85 a.a.

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: nucleus (3 terms)
• Biological process: intracellular signal transduction (10 terms)
• Biochemical function: protein binding (1 term)

DOI no: 10.1016/j.str.2007.09.016

Structure 15:1493-1504 (2007)

PubMed id: 17997974

Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation.

A.N.Bullock, M.C.Rodriguez, J.E.Debreczeni, Z.Songyang, S.Knapp.

ABSTRACT

Tyrosine kinase signaling is tightly controlled by negative feedback inhibitors including suppressors of cytokine signaling (SOCS). SOCS assemble as SH2 domain substrate recognition modules in ElonginB/C-cullin ubiquitin ligases. In accordance, SOCS4 reduces STAT3 signaling from EGFR through increased receptor degradation. Variable C-termini in SOCS4-SOCS7 exclude these family members from a SOCS2-type domain arrangement in which a strictly conserved C terminus determines domain packing. The structure of the SOCS4-ElonginC-ElonginB complex reveals a distinct SOCS structural class. The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.

Selected figure(s)

Figure 2.
Figure 2. Structural Comparison of the SH2 Substrate Pockets in SOCS2, SOCS3, and SOCS4
(A) Overlay of the crystal structures of the SOCS4 SH2 (orange) and the SOCS2 SH2 (blue, PDB code: 2C9W). The binding site of the phosphotyrosine moiety in SOCS2 is indicated by the presence of a bound sulfate ion. SOCS4 residues at this site are shown in ball-and-stick representation with their potential hydrogen bonding.
(B) Overlay of the crystal structures of the SOCS4 SH2 (orange) and the murine SOCS3 gp130 complex (blue, PDB code: 2HMH). The phosphotyrosine and three C-terminal residues from the murine gp130-derived peptide are colored green. N-terminal tag residues from a crystallographic SOCS4 neighbor occupy the same SH2 pocket in the SOCS4 structure forming substrate mimetic interactions and are colored yellow.
(C) Surface representation of the SH2 substrate pocket in SOCS2, SOCS3, and SOCS4 colored by electrostatic potential. The bound sulfate ion identifies the phosphotyrosine binding site in SOCS2 (left). The gp130 peptide is shown in complex with SOCS3 (center) and docked onto the SOCS4 surface (right) by the overlay of the two structures (for SOCS4 only the gp130 residues corresponding to the pY−1 to pY+3 positions are shown).

Figure 3.
Figure 3. Alternative Domain Organization in the SOCS2 and SOCS4 Ternary Complexes
(A) Comparison of the SOCS2-ElonginB/ElonginC and SOCS4-ElonginB/ElonginC structures highlighting the switch in packing between the SOCS2/SOCS4 C terminus and the N-terminal ESS helix (colored as in Figure 1).
(B) Molecular interactions stabilizing the domain organization in SOCS4.
(C) Structural overlay of the SOCS2 and SOCS4 SOCS box showing an 80° rotation of the SOCS4 SH2 domain relative to the SOCS2 SH2. The positions of the SOCS2 and SOCS4 phosphotyrosine pockets are indicated by a SOCS2-bound sulfate ion and a SOCS4-bound phosphotyrosine (modeled as in Figure 2). For clarity, the SOCS2 ESS is omitted and only the N-terminal half of each SH2 domain is shown. An asterisk denotes the position of the hinge point for rotation which occurs at R383/T384 in SOCS4.
(D) Structural overlay of the SOCS2 and SOCS4 SH2 domains showing the alternative packing sites for the respective SOCS box domains on opposite faces of the ESS and SH2. The SOCS2-bound sulfate ion indicates the position of the SH2 phosphotyrosine pocket.

The above figures are reprinted from an Open Access publication published by Cell Press: Structure (2007, 15, 1493-1504) copyright 2007.

Figures were selected by the author.

Author's comment

An animated version of the structure (active Isee) as well as detailed description of material and methods is also available on our website: http://www.sgc.ox.ac.uk/structures/XX10SOCS2A_2c9w.html.