HEИндивидуална стипендия2023–2025

GlutaMature · Engineering and structure of transient ionotropic glutamate receptor complexes

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-09-01 → 2025-08-31
Финансиране от ЕС: 195 915 €
Участници: 2
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Рецепторите за глутамат в мозъка и техните връзки с външни протеини определят как се предава сигналът между невроните. Разбирането на тези структури помага да се разбере паметта и да се открият нови начини за лечение на невродегенеративни заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Engineering and structure of transient ionotropic glutamate receptor complexes

Communication between neuronal cells is performed by cellular junctions called synapses. A hallmark of synapses is their ability to change their potency of signal transmission in response to patterns of neuronal activity, which is known as “synaptic plasticity”, a process that is important for allowing long-term information storage. Signal transmission through synapses is mediated by ligand-gated ion channels at the postsynapse, called ionotropic glutamate receptors (iGluRs), that are activated by the neurotransmitter glutamate. Multiple regulatory mechanisms control the magnitude of this postsynaptic response, such as the channel properties as well as the number and spatial positioning of the receptors. An important but not well studied mechanism is the regulation of iGluRs interact by extracellular proteins, notably adhesion molecules and synaptic organizer proteins, which modulate iGluR location and function. Despite their capital importance, the mechanism of iGluR modulation by synaptic organizer proteins remains highly unexplored. The goal of this proposal was to elucidate the assembly of two iGluR subclasses (AMPA and GluD receptors) with extracellular scaffolding proteins. To this end, we aimed to determine the structure of AMPARs in complex with ESPs via protein engineering and biophysical/structural methods. This integrative structural biology approach should reveal general structural principles of iGluR regulation by ESPs which will aid in understanding the role of ESPs in synaptic plasticity and could uncover novel therapeutic avenues for neurodegenerative diseases.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

All aspects of brain function rely on the interplay between networks of functionally related neuronal cells. These cells are connected by “synapses”, which are specialized cellular compartments dedicated to rapid electrical and chemical signalling. Excitatory neurotransmission in the vertebrate central nervous system (CNS) is largely mediated by the ionotropic glutamate receptors (iGluRs). These postsynaptic receptors conduct cations into the cell in response to binding of the neurotransmitter glutamate released from presynaptic vesicles. Accumulation and positioning of iGluRs at neuronal synapses are crucial for enabling correct neurotransmission. While it is known that extracellular scaffolding proteins (ESPs) interact with iGluRs to stabilize these receptors at synapses, the transient, low-affinity nature of these protein interactions has so far precluded complex structure determination and therefore a precise mechanistic understanding of their function. The aim of this proposal is to implement state-of-the-art techniques of protein engineering to stabilise iGluR:ESP interactions for structure determination by affinity maturation of their interaction interfaces. I will focus on two well-established complexes: Cerebellin-Glutamate receptor Delta (Cbln-GluD) and Neuronal Pentraxin-AMPA receptor (NP-AMPAR). Structural insights into the full-length synapse-spanning Cbln-GluD and NP-AMPAR interactions will elucidate how clustering and trans-synaptic anchoring of iGluRs contribute to synaptic transmission, as well as pave the way for the design of engineered synaptic organizer proteins capable of remodelling synapses. During this project I will gain experience in protein engineering which will allow me to establish a career as an independent scientist with a focus on tackling complex structural biology problems with translational applications.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция
UNIVERSITE DE BORDEAUX · BordeauxФранция