PMID- 10078535
OWN - NLM
STAT- MEDLINE
DCOM- 19990325
LR  - 20161124
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 398
IP  - 6722
DP  - 1999 Mar 4
TI  - Structure of the amino-terminal domain of Cbl complexed to its binding site on
      ZAP-70 kinase.
PG  - 84-90
AB  - Cbl is an adaptor protein that functions as a negative regulator of many
      signalling pathways that start from receptors at the cell surface. The
      evolutionarily conserved amino-terminal region of Cbl (Cbl-N) binds to
      phosphorylated tyrosine residues and has cell-transforming activity. Point
      mutations in Cbl that disrupt its recognition of phosphotyrosine also interfere
      with its negative regulatory function and, in the case of v-cbl, with its
      oncogenic potential. In T cells, Cbl-N binds to the tyrosine-phosphorylated
      inhibitory site of the protein tyrosine kinase ZAP-70. Here we describe the
      crystal structure of Cbl-N, both alone and in complex with a phosphopeptide that 
      represents its binding site in ZAP-70. The structures show that Cbl-N is composed
      of three interacting domains: a four-helix bundle (4H), an EF-hand
      calcium-binding domain, and a divergent SH2 domain that was not recognizable from
      the amino-acid sequence of the protein. The calcium-bound EF hand wedges between 
      the 4H and SH2 domains and roughly determines their relative orientation. In the 
      ligand-occupied structure, the 4H domain packs against the SH2 domain and
      completes its phosphotyrosine-recognition pocket. Disruption of this binding to
      ZAP-70 as a result of structure-based mutations in the 4H, EF-hand and SH2
      domains confirms that the three domains together form an integrated
      phosphoprotein-recognition module.
FAU - Meng, W
AU  - Meng W
AD  - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
      School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
FAU - Sawasdikosol, S
AU  - Sawasdikosol S
FAU - Burakoff, S J
AU  - Burakoff SJ
FAU - Eck, M J
AU  - Eck MJ
LA  - eng
SI  - PDB/1B47
SI  - PDB/2CBL
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Phosphopeptides)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
RN  - EC 2.7.10.2 (ZAP70 protein, human)
RN  - EC 6.3.2.- (CBL protein, human)
SB  - IM
CIN - Nature. 1999 Mar 4;398(6722):22-3, 25. PMID: 10078523
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Escherichia coli
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Phosphopeptides/chemistry/metabolism
MH  - Protein Conformation
MH  - Protein-Tyrosine Kinases/*chemistry/metabolism
MH  - Proto-Oncogene Proteins/*chemistry/metabolism
MH  - Proto-Oncogene Proteins c-cbl
MH  - Recombinant Fusion Proteins/chemistry/metabolism
MH  - Sequence Homology, Amino Acid
MH  - *Ubiquitin-Protein Ligases
MH  - ZAP-70 Protein-Tyrosine Kinase
MH  - src Homology Domains
EDAT- 1999/03/17 03:05
MHDA- 2001/03/23 10:01
CRDT- 1999/03/17 03:05
PHST- 1999/03/17 03:05 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/03/17 03:05 [entrez]
AID - 10.1038/18050 [doi]
PST - ppublish
SO  - Nature. 1999 Mar 4;398(6722):84-90. doi: 10.1038/18050.