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Title: Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11)

Journal Article · · BMC Structural Biology (Online)
 [1];  [2];  [1];  [1];  [1];  [1];  [3];  [4];  [2];  [5]
  1. Univ. Health Network, Toronto, ON (Canada). Princess Margaret Center
  2. Univ. Health Network, Toronto, ON (Canada). Princess Margaret Center; Univ. of Toronto, ON (Canada). Dept. of Medical Biophysics
  3. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS). Hauptman-Woodward Medical Research Inst, IMCA-CAT
  4. Univ. Health Network, Toronto, ON (Canada). Princess Margaret Center; Univ. of Toronto, ON (Canada). Dept. of Biochemistry, Molecular Genetics and Medical Biophysics
  5. Univ. Health Network, Toronto, ON (Canada). Princess Margaret Center; Univ. of Toronto, ON (Canada). Dept. of Pharmacology and Toxicology
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Ontario Research and Development Challenge Fund; Canada Research Chairs Program; Ontario Ministry of Health and Long Term Care; The Princess Margaret Cancer Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1626548
Journal Information:
BMC Structural Biology (Online), Vol. 14, Issue 1; ISSN 1472-6807
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (6)

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations journal March 2020
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 journal October 2018
Low-dose dasatinib rescues cardiac function in Noonan syndrome journal December 2016
The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway journal June 2018
Exploring the effect of N308D mutation on protein tyrosine phosphatase‐2 cause gain‐of‐function activity by a molecular dynamics study journal October 2018
Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines journal June 2016

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
71 CLASSICAL AND QUANTUM MECHANICS
GENERAL PHYSICS
Biophysics
Noonan Syndrome
PTPN11 Mutation
Juvenile Myelomonocytic Leukemia
Leopard Syndrome
Local Conformational Change