5bk8

Cancer-associated SHP2/T507K mutantCancer-associated SHP2/T507K mutant

Structural highlights 5bk8 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: PTPN11, PTP2C, SHPTP2 (HUMAN) Activity: Protein-tyrosine-phosphatase, with EC number 3.1.3.48 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 protein tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors.Mutations in the SHP2gene have beenlinked to many different types of human diseases, including developmental disorders, leukemia and solid tumors.Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the wild-type enzyme, the interactions between its N-SH2 and PTP domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enables the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity. Mechanistic insights explain the transforming potential of the T507K substitution in the protein tyrosine phosphatase SHP2.,Zhang RY, Yu ZH, Chen L, Walls CD, Zhang S, Wu L, Zhang ZY J Biol Chem. 2020 Mar 18. pii: RA119.010274. doi: 10.1074/jbc.RA119.010274. PMID:32188694 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 5bk8, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image