4ohe

LEOPARD Syndrome-Associated SHP2/G464A mutant

spinqualitylabelsall models 4ohe, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ohe is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.506Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PTN11_HUMAN Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness. Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant. Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM:156250. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions. Function PTN11_HUMAN Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity. Publication Abstract from PubMed The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme's catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations.,Yu ZH, Zhang RY, Walls CD, Chen L, Zhang S, Wu L, Liu S, Zhang ZY Biochemistry. 2014 Jul 1;53(25):4136-51. doi: 10.1021/bi5002695. Epub 2014 Jun, 17. PMID:24935154 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine phosphatase 3D structures

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