title: Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11).
abstract: BACKGROUND
  The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders.
  
  
  RESULTS
  Although multiple studies have reported the biochemical and biological consequences of NS- and LS-associated PTPN11 mutations, their structural consequences have not been analyzed fully. Here we report the crystal structures of WT SHP2 and five NS/LS-associated SHP2 mutants. These findings enable direct structural comparisons of the local conformational changes caused by each mutation.
  
  
  CONCLUSIONS
  Our structural analysis agrees with, and provides additional mechanistic insight into, the previously reported catalytic properties of these mutants. The results of our research provide new information regarding the structure-function relationship of this medically important target, and should serve as a solid foundation for structure-based drug discovery programs.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Vladimir
authors.initials: V
authors.lastname: Romanov
authors.forename: Ashley
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Andrés
authors.initials: A
authors.lastname: Lin
authors.forename: Maxim
authors.initials: M
authors.lastname: Ruzanov
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Battaile
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, M5G 2C4, Canada. bneel@uhnresearch.ca.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Nickolay Y
authors.initials: NY
authors.lastname: Chirgadze
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry* / Q000235:genetics*
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11