PDBsum entry 2bz8

Sh3 domain

PDB id: 2bz8

Contents

Protein chains

57 a.a. *

11 a.a. *

Metals

_NA ×2

Waters ×82

* Residue conservation analysis

PDB id:

2bz8

Name:

Sh3 domain

Title:

N-terminal sh3 domain of cin85 bound to cbl-b peptide

Structure:

Sh3-domain kinase binding protein 1. Chain: a, b. Fragment: n-terminal sh3 domain residues 1-58. Synonym: cbl-interacting protein of 85kda, human src-family kinase binding protein 1, hsb-1, cd2 binding protein 3, cd2bp3, cin85. Engineered: yes. Signal transduction protein cbl-b sh3-binding protein cbl- b, ring finger protein 56, cbl-b. Chain: c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: brain, kidney, heart, placenta, lung, liver, skeletal muscle, pancreas. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.00Å R-factor: 0.221 R-free: 0.271

Authors:

N.Cardenes,G.Moncalian,J.Bravo

Key ref:

D.Jozic et al. (2005). Cbl promotes clustering of endocytic adaptor proteins. Nat Struct Biol, 12, 972-979. PubMed id: 16228008 DOI: 10.1038/nsmb1000

Date:

12-Aug-05 Release date: 05-Oct-05

Protein chains

Q96B97  (SH3K1_HUMAN) -  SH3 domain-containing kinase-binding protein 1 from Homo sapiens

Seq: 665 a.a.

Struc: 57 a.a.

Protein chain

Q13191  (CBLB_HUMAN) -  E3 ubiquitin-protein ligase CBL-B from Homo sapiens

Seq: 982 a.a.

Struc: 11 a.a.

Enzyme reactions

• Enzyme class: Chain C: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

DOI no: 10.1038/nsmb1000

Nat Struct Biol 12:972-979 (2005)

PubMed id: 16228008

Cbl promotes clustering of endocytic adaptor proteins.

D.Jozic, N.Cárdenes, Y.L.Deribe, G.Moncalián, D.Hoeller, Y.Groemping, I.Dikic, K.Rittinger, J.Bravo.

ABSTRACT

The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation. Their function is modulated through interactions with regulatory proteins including CIN85 and PIX, which recognize a proline-arginine motif in Cbl and thus promote or inhibit receptor endocytosis. We report the structures of SH3 domains of CIN85 and beta-PIX in complex with a proline-arginine peptide from Cbl-b. Both structures reveal a heterotrimeric complex containing two SH3 domains held together by a single peptide. Trimerization also occurs in solution and is facilitated by the pseudo-symmetrical peptide sequence. Moreover, ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation. These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation.

Selected figure(s)

Figure 2.
Figure 2. Overall structure of the -PIX–Cbl-b and CIN85A–Cbl-b heterotrimeric complexes and details of the protein-peptide contacts. (a,b) The biologically relevant heterotrimeric complex of -PIX and Cbl-b (a, green) and the trimeric complex of CIN85A and Cbl-b (b, blue). The electron density map around the peptide is contoured at 2.5 . The secondary structural elements and position of the RT, n-Src and distal loops are indicated. Both structures are shown in the same orientation to highlight their similarity. The peptide in the CIN85A complex shows additional density for residues Ala903, Pro902 and Arg912, which are disordered in the PIX complex. (c,d) A schematic representation of the protein-peptide contacts between the Cbl peptide and -PIX (c) and CIN85A (d). Green, PIX–Cbl-b peptide; blue, CIN85–Cbl-b peptide; black, residues from -PIX and CIN85A; dashed lines, hydrogen bonds (labeled with peptide-protein distances in Å); black rays, hydrophobic interactions. SH3 domains are indicated in parentheses.

Figure 5.
Figure 5. Comparison of the ternary -PIX–Cbl-b complex with a SuperSH3 domain. Stereo representation of the overlaid backbones of SH3B from the -PIX–Cbl-b complex (green) and the p47–p22^phox structure (orange).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2005, 12, 972-979) copyright 2005.

Figures were selected by the author.