PDBsum entry 4dgx

Hydrolase

PDB id: 4dgx

Contents

Protein chain

501 a.a.

Waters ×183

PDB id:

4dgx

Name:

Hydrolase

Title:

Leopard syndrome-associated shp2/y279c mutant

Structure:

Tyrosine-protein phosphatase non-receptor type 11. Chain: a. Fragment: n-sh2, c-sh2, and ptp domains (unp residues 1-532). Synonym: src homology 2 (sh2)-domain containing protein tyrosine phosphatase-2, shp2, protein-tyrosine phosphatase 1d, ptp-1d, protein-tyrosine phosphatase 2c, ptp-2c, sh-ptp2, shp-2, sh-ptp3. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn11, ptp2c, shptp2. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.212 R-free: 0.266

Authors:

Z.H.Yu,J.Xu,C.D.Walls,L.Chen,S.Zhang,L.Wu,L.N.Wang,S.J.Liu,Z.Y.Zhang

Key ref:

Z.H.Yu et al. (2013). Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J Biol Chem, 288, 10472-10482. PubMed id: 23457302 DOI: 10.1074/jbc.M113.450023

Date:

27-Jan-12 Release date: 06-Mar-13

Protein chain

Q06124  (PTN11_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens

Seq: 593 a.a.

Struc: 501 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.3.48 - protein-tyrosine-phosphatase.
• Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1074/jbc.M113.450023

J Biol Chem 288:10472-10482 (2013)

PubMed id: 23457302

Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations.

Z.H.Yu, J.Xu, C.D.Walls, L.Chen, S.Zhang, R.Zhang, L.Wu, L.Wang, S.Liu, Z.Y.Zhang.

ABSTRACT

SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD syndrome mutations weaken the intramolecular interaction between the N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases.