PDBsum entry 3vgo

Ligase

PDB id

3vgo

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Contents

			Protein chain

					287 a.a.

PDB id:

3vgo

Links

Name:

Ligase

Title:

Crystal structure of the n-terminal fragment of cbl-b

Structure:

E3 ubiquitin-protein ligase cbl-b. Chain: a, b, c. Fragment: n-terminal fragment, unp residues 39-426. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cblb. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

3.10Å

R-factor:

0.270

R-free:

0.328

Authors:

Y.Kobashigawa,N.N.Noda,F.Inagaki

Key ref:

Y.Kobashigawa et al. (2011). Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b. Proc Natl Acad Sci U S A, 108, 20579-20584. PubMed id: 22158902

Date:

18-Aug-11

Release date:

14-Dec-11

PROCHECK

	Headers

	References

Protein chains

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

Seq: Struc:

Seq: Struc:					982 a.a. 287 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

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

	Proc Natl Acad Sci U S A 108:20579-20584 (2011)
PubMed id: 22158902

Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b.
Y.Kobashigawa, A.Tomitaka, H.Kumeta, N.N.Noda, M.Yamaguchi, F.Inagaki.

ABSTRACT

Cbl-b is a RING-type E3 ubiquitin ligase that functions as a negative regulator of T-cell activation and growth factor receptor and nonreceptor-type tyrosine kinase signaling. Cbl-b dysfunction is related to autoimmune diseases and cancers in humans. However, the molecular mechanism regulating its E3 activity is largely unknown. NMR and small-angle X-ray scattering analyses revealed that the unphosphorylated N-terminal region of Cbl-b forms a compact structure by an intramolecular interaction, which masks the interaction surface of the RING domain with an E2 ubiquitin-conjugating enzyme. Phosphorylation of Y363, located in the helix-linker region between the tyrosine kinase binding and the RING domains, disrupts the interdomain interaction to expose the E2 binding surface of the RING domain. Structural analysis revealed that the phosphorylated helix-RING region forms a compact structure in solution. Moreover, the phosphate group of pY363 is located in the vicinity of the interaction surface with UbcH5B to increase affinity by reducing their electrostatic repulsion. Thus, the phosphorylation of Y363 regulates the E3 activity of Cbl-b by two mechanisms: one is to remove the masking of the RING domain from the tyrosine kinase binding domain and the other is to form a surface to enhance binding affinity to E2.

Literature references that cite this PDB file's key reference

PubMed id

Reference

22266821

H.Dou, L.Buetow, A.Hock, G.J.Sibbet, K.H.Vousden, and D.T.Huang (2012).
Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl.

Nat Struct Mol Biol, 19, 184-192.

PDB codes:

2y1m 2y1n 4a49 4a4b 4a4c

22301873

S.C.Kales, P.E.Ryan, and S.Lipkowitz (2012).
Cbl exposes its RING finger.

Nat Struct Mol Biol, 19, 131-133.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.