Mechanism of allosteric regulation of SHP2 phosphatase and its role in cancer and genetic diseases: a multidisciplinary computational, structural and biological approach

Información del proyecto

MARS

Identificador del acuerdo de subvención: 705829

DOI

10.3030/705829

Proyecto cerrado

Fecha de la firma de la CE 15 Julio 2016

Fecha de inicio 1 Abril 2017

Fecha de finalización 31 Marzo 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 159 460,80

Aportación de la UE

€ 159 460,80

Coordinado por

GEORG-AUGUST-UNIVERSITAT GOTTINGEN STIFTUNG OFFENTLICHEN RECHTS
Germany

Objetivo

SHP2 is an SH2 domain-containing protein tyrosine phosphatase with a key role in the RAS-MAPK signaling pathway. Germline mutations in PTPN11, the gene encoding SHP2, occur in 50% of individuals affected by Noonan syndrome, whereas somatic mutations in this gene cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML), and are more rarely found in other hematologic malignancies and tumors.
The X-ray structure of SHP2 shows a multidomain architecture compatible with an allosteric regulatory mechanism: under basal conditions SHP2 is inactive, because its N-terminal Src homology 2 (N-SH2) domain blocks the active site of the protein tyrosine phosphatase (PTP) domain. Binding of the N-SH2 domain to a phosphopeptide (PP) ligand causes SHP2 activation by favoring dissociation of the N-SH2 and PTP domains.
To characterize this dynamic transition at the atomic level, will be used a combination of state of the art computational methods coupled to X-ray scattering (XS) and biochemical assays. Major goals of the proposed studies are to explain how disease-associated mutations perturb the regulatory events controlling SHP2 function, and design new molecules able to inhibit SHP2 binding to signaling partners.
The project implementation is guaranteed by the expertise of the Experienced Researcher (ER) in molecular dynamics (MD) studies of allosteric mechanisms that is complemented by the consolidated expertise of the host institution (HI) in the combined use of MD and XS, together with the external collaboration of an Italian expert in SHP2 biology and a US specialist in XS. Overall, the proposed research will provide a deeper understanding of SHP2 regulation, and dissect the molecular mechanisms implicated in its functional dysregulation in human disease. The planned studies are expected to provide a new class of lead compounds to treat SHP2-associated diseases. Finally, a new computational approach for the design of peptidomimetic inhibitors will be developed.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › informática y ciencias de la información › ciencias de la computación
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › medicina clínica › oncología › leucemia

Palabras clave

• Molecular dynamics simulations
• Allosteric regulation in proteins
• Protein tyrosine phosphatases
• Genetic diseases
• Noonan syndrome
• RASopathies

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2015

Coordinador

GEORG-AUGUST-UNIVERSITAT GOTTINGEN STIFTUNG OFFENTLICHEN RECHTS

• Aportación neta de la UEn: € 159 460,80
• Dirección: WILHELMSPLATZ 1 ; 37073 Gottingen ; Alemania
• Región: Niedersachsen › Braunschweig › Göttingen
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 159 460,80