CryoEm structure of gamma secretase: a key component in Alzheimer neurodegenerative disease

Objective

Alzheimer disease (AD) is characterised by the accumulation of beta amyloid peptide cut from a transmembrane precursor. A large intramembrane complex carries out the proteolysis: gamma-secretase, containing the protease presenilin and other three proteins (nicastrin, aph1, pen2). G-secretase is involved also in the proteolysis mediated signaling cascade by the transmembrane receptors Notch1 and Erb4, regulating cell growth and differentiation The aim of the project is to gain structural insight into the architecture of the g-secretase and its mutant variants involved in AD by cryo-Electron Microscopy (EM) and into substrate binding by 2D electron crystallography; 3D X-ray crystal structure of presenilin will be fit in EM map Getting structural information of g-secretase is important at cellular level (involvement in signal transduction pathways), structural (few membrane protein structures described), biochemical (intramembrane proteolysis) and biomedical (involvement in a widespread neurodegenerative disease) The project will be developed in USA in EM lab of Prof Ubarretxena Belandia (NYSBC and Mount Sinai SM) in collaboration with Prof Sisodia (Dept Neurobiology Univ of Chicago) providing purified g-secretase and performing functional studies. Return host is the Univ of Rome La Sapienza (Dept Biochem Sciences, Biocrystallography Unit, Prof Vallone) Structural and structural-dynamic studies are progressively focusing on larger macromolecular complexes: for these crystallography is demanding in purification and crystallization, meanwhile cryoEM is becoming the election technique The fellow will bring back to Rome know-how in cryoEM and 2D crystallography to study structures and dynamics of large assemblies to be integrated with 3D X-ray crystallography of single subunits. He will develop as independent researcher contributing to the progress of group in Rome and to build a solid intercontinental collaboration with a state of the art institution

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.

• natural sciences biological sciences neurobiology
• medical and health sciences basic medicine neurology dementia alzheimer
• natural sciences earth and related environmental sciences geology mineralogy crystallography
• natural sciences biological sciences biochemistry biomolecules proteins
• natural sciences physical sciences optics microscopy

Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

• 2D electron
• Alzheimer
• Cryo-Electron Microscopy
• gamma secretase

Programme(s)

Multi-annual funding programmes that define the EU’s priorities for research and innovation.

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

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.

• PEOPLE-2007-4-1.IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development"

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-2007-4-1-IOF
See other projects for this call

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.

MC-IOF - International Outgoing Fellowships (IOF)

Coordinator