Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences computer and information sciences computational science
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology leukemia
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
-
H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
See all projects funded under this programme -
H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
See all projects funded under this programme
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
See all projects funded under this funding scheme
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2015
See all projects funded under this callCoordinator
Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
37073 Gottingen
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.