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Home > Research Leaders > A to G > Radu Aricescu
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Radu Aricescu

The structural biology of synaptic connectivity

radu@mrc-lmb.cam.ac.uk
Cryo-EM structure of a human GABA<sub>A</sub> receptor
Cryo-EM structure of a human GABAA receptor (Laverty et al, 2019; Masiulis et al, 2019).

Neuronal circuits are the biological substrates for all aspects of brain function such as learning, memory, thought, speech and consciousness. The synapses, connecting points between neurons, are continuously remodelled in response to novel experiences and hold the key to understanding how these circuits work.

Little is known, however, about the fine structure of synapses. Increasingly long lists of molecular components are available and we know how some of these look in atomic detail, typically in isolation. However, these players do not work alone. They must come together and coordinate to make a functional synapse.

We employ a combination of structural biology methods, including X-ray crystallography, electron cryo-microscopy and tomography, to define in high-resolution the architecture of neurotransmitter receptors, their supra-molecular assemblies and, eventually, whole synapses. We aim to link structural work with neuronal physiology, in order to provide fundamental mechanistic insights into the basic biology of neurotransmission.

This work is also relevant for medicine. Normal human ageing as well as the majority of psychiatric and neurological disorders, from mental retardation and autism to Alzheimer’s disease and addiction, are caused by errors in synaptic signalling and reduction in synapse numbers. We aim to use structural information to devise molecular tools that can help repair damaged synapses and restore their physiological function.

Structure-guided design of CPTX, a synthetic synaptic organiser (Suzuki et al, 2020).
Structure-guided design of CPTX, a synthetic synaptic organiser (Suzuki et al, 2020).
https://www2.mrc-lmb.cam.ac.uk/wordpress/wp-content/uploads/Ariescu_ior_8-20_Movie_1_ataxia.mp4

Mouse model of cerebellar ataxia, before and after CPTX injection (Suzuki et al, 2020).

Selected Papers

  • Suzuki, K., Elegheert, J., Song, I., Sasakura, H., Senkov, O., Kakegawa, W., Clayton, AJ., Chang, VT., Ferrer-Ferrer, M., Miura, E., Kaushik, R., Ikeno, M., Morioka, Y., Takeuchi, Y., Shimada, T., Otsuka, S., Stoyanov, S., Watanabe, M., Takeuchi, K., Dityatev, A., Aricescu, AR., Yuzaki, M. (2020)
    A synthetic synaptic organizer protein restores glutamatergic neuronal circuits.
    Science 369(6507): eabb4853. doi:10.1126/science.abb4853
  • Masiulis S, Desai R, Uchański T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR. (2019)
    GABAA receptor signalling mechanisms revealed by structural pharmacology
    Nature, doi: 10.1038/s41586-018-0832-5.
  • Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR (2019)
    Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer.
    Nature, doi: 10.1038/s41586-018-0833-4.
  • Elegheert, J., Cvetkovska, V., Clayton, A.J., Heroven, C., Vennekens, K.M., Smukowski, S.N., Regan, M.C., Jia, W., Smith, A.C., Furukawa, H., Savas, J.N., de Wit, J., Begbie, J., Craig, A.M. and Aricescu, A.R. (2017)
    Structural mechanism for modulation of synaptic neuroligin-neurexin signalling by MDGA proteins.
    Neuron 95: 896-913.
  • Elegheert, J., Kakegawa, W., Clay, J.E., Shanks, N.F,, Behiels, E., Matsuda, K., Kohda, K., Miura, E., Rossmann, M., Mitakidis, N., Motohashi, J., Chang, V.T., Siebold, C., Greger, I., Nakagawa, T., Yuzaki, M. and Aricescu, A.R. (2016)
    Structural Basis for Integration of GluD Receptors within Synaptic Organizer Complexes.
    Science 353: 295-299.
  • Miller, P.S. and Aricescu, A.R. (2014)
    Crystal structure of a human GABAA receptor.
    Nature 512: 270-275.

Group Members

  • Veronica Chang
  • Christina Heroven
  • Vikram Kasaragod
  • Lina Malinauskaite
  • Jonas Miehling
  • Daniel Mihaylov
  • Andrija Sente
  • Anirudh Sharma
  • Kunimichi Suzuki

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Research Leaders

  • A to G
    • Radu Aricescu
    • David Barford
    • Buzz Baum
    • Anne Bertolotti
    • Mariann Bienz
    • John Briggs
    • Simon Bullock
    • Albert Cardona
    • Andrew Carter
    • Jason Chin
    • Gerry Crossan
    • Emmanuel Derivery
    • Benjamin Falcon
    • Michel Goedert
    • Julian Gough
    • Ingo Greger
  • H to M
    • Michael Hastings
    • Ramanujan Hegde
    • Richard Henderson
    • Philipp Holliger
    • Leo James
    • Gregory Jefferis
    • Patrycja Kozik
    • Madeline Lancaster
    • Jan Löwe
    • Kate McDole
    • Andrew McKenzie
    • Harvey McMahon
    • Liz Miller
    • Sean Munro
    • Garib Murshudov
  • N to S
    • Kiyoshi Nagai (1949-2019)
    • David Neuhaus
    • Kelly Nguyen
    • John O’Neill
    • Lori Passmore
    • Venki Ramakrishnan
    • Felix Randow
    • Jing Ren
    • Katja Röper
    • Christopher Russo
    • Julian Sale
    • William Schafer
    • Sjors Scheres
    • Marta Shahbazi
    • John Sutherland
  • T to Z
    • Chris Tate
    • Rebecca Taylor
    • Marco Tripodi
    • Ana Tufegdžić Vidaković
    • Roger Williams
    • Joseph Yeeles
    • Marta Zlatic
  • Emeritus
    • Brad Amos
    • Tony Crowther
    • Phil Evans
    • Alan Fersht
    • Michael Gait
    • Rob Kay
    • John Kendrick-Jones
    • John Kilmartin
    • Peter Lawrence
    • Andrew Leslie
    • Hugh Pelham
    • Daniela Rhodes
    • Murray Stewart
    • Andrew Travers
    • Nigel Unwin
    • Greg Winter
  • LMB Fellows
  • Molecular Immunity Unit

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