SorCS · Structural and biophysical characterisation of insulin receptor and glutamate receptors AMPAR and NMDAR in complex with SorCS coreceptors 1 and 2
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-05-01 → 2024-04-30
- EU contribution
- €214,934
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Structural and biophysical characterisation of insulin receptor and glutamate receptors AMPAR and NMDAR in complex with SorCS coreceptors 1 and 2
Sortilin related CNS expressed receptor (SorCS) 1, 2 and 3, members of the Vacuolar Protein Sorting 10 protein (VPS10p) family, are neural sorting receptors that play a central role in control of neuronal viability and function by sorting crucial proteins. Reduced trafficking of the NMDA receptor to the cell membrane surface has previously been reported in SorCS deficient mice and linked to neurodegenerative diseases. However, the molecular mechanism for SorCS mediated NMDAR trafficking is still unknown. We show that co-expression of NMDAR and SorCS1 or SorCS2 increase the NMDA current linked to higher NMDAR cell surface expression. Subunit N2B interacts with SorCS1 and SorCS2, as the NMDA current is significantly impaired when the N2B tail is truncated. Our findings show that SorCS 1, 2 and 3 interact subunit specific with the C-terminal tail of NMDAR, thus suggest different trafficking routes of NMDAR sorting. The different regulation and pathways of NMDAR by SorCS members can make it an intersting therapeutic target for neurodegenerative diseases.
Data: CORDIS, © European Union
Project objective
Type II diabetes (T2D), Alzheimer’s Disease (AD) and Parkinson’s disease (PD) are common age-related diseases, which have reached endemic levels and become a burden for the global health. Lifestyle and environment are risk factors, but cannot explain all cases - genes also predispose for these diseases. Common for T2D, AD and PD is abnormal cell function associated with dysfunction of insulin receptor, AMPA receptor or NMDA receptor. The Vacuolar Protein Sorting 10 protein (VPS10P) family contain five neural type 1 transmembrane sorting receptors: sortilin, SorLA, SorCS1, SorCS2 and SorCS3, that play a central role in control of neuronal viability and function by sorting crucial proteins. SorCS1 and SorCS2 interact with and sort IR, AMPAR and NMDAR, and genetic deficiencies for SorCS1 and -2 are associated with accelerated onset of pathology, thus implicating these receptors as critical regulators for normal cell function. However, the molecular mechanisms of SorCS1 and SorCS2 mediated sorting of target receptors are not known, and with this proposal I want to determine structures and investigate interactions of SorCS1:IR, SorCS1:AMPAR and SorCS2:NMDAR complexes. Determining the structures of transmembrane SorCS1:IR, SorCS1:AMPAR and SorCS2:NMDAR complexes by cryogenic electron microscopy (cryo-EM) we will reveal molecular details about the interaction such as the role of interacting elements at cytoplasmic tails, transmembrane helices and exodomains, and how they define specificity (SorCS1 vs. SorCS2), function and regulation. The proposed project can define new positions and in translational research that aims for drug discovery for T2D, AD and PD.
Original text from CORDIS.
Participants
- AARHUS UNIVERSITET · Aarhus CCoordinatorDenmark
Links
- View on CORDIS
- DOI: 10.3030/101060987
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50acd019b&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5f3c5296f&appId=PPGMS
Data: CORDIS, © European Union