725 N. Wolfe Street, WBSB 713
Baltimore, MD 21205-2185
Research topics: Cryo-electron microscopy, membrane proteins, glutamate receptors, protein homeostasis
We are interested in the structural and biochemical underpinnings of neurotransmission and neurodegeneration, as well as the homeostasis of the proteins contributing to these processes. Primarily, we will be applying cryo-electron microscopy (cryo-EM) to reconstruct the biochemical processes underlying these problems. We firmly believe that the most informative mechanistic insights into biology come from a deep understanding of the biological machines that govern them.
In particular, we are interested in AMPA receptors, which dictate fast excitatory neurotransmission and are thus responsible for the initial depolarization of the post-synaptic neuron. AMPA receptor complexes at the post-synaptic membrane, and the dynamics of their recruitment to, and removal from it, have profound effects on synaptic plasticity – the process by which patterns of synaptic activity result in a strengthening or weakening of transmission. The altered neurotransmission affects high cognitive processes such as learning and memory, and its dysregulation leads to neurodegeneration.
A second area of focus is protein quality control and recycling, which are essential for cell viability and life. We are particularly interested in how AAA+ ATPases and their co-factors alter neuronal protein homeostasis, with an emphasis on impacting receptor homeostasis. We aim to characterize these processes biochemically through in vitro reconstitution and reconstruct them structurally with cryo-EM. These data will provide new insights into neuronal protein homeostasis, structure-function relationships, and lay foundations for rational drug design.
Twomey, E.C.*, Ji, Z.*, Wales, T.E., Bodnar, N.O., Ficarro, S.B., Marto, J.A., Engen, J.R., Rapoport, T.A. “Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.” Science, Aug 2;365(6452). pii: eaax1033. PMID: 31249135.
Twomey, E.C., Yelshanskaya, M.V., Vassilevski, A.A., Sobolevsky, A.I. “Mechanisms of channel block in calcium-permeable AMPA receptors.” Neuron, 99: 956-968 (2018). PMID: 30122377. Featured as issue cover.
Twomey, E.C., Yelshanskaya, M.V., Grassucci, R.A., Frank, J., Sobolevsky, A.I. “Channel opening and gating mechanism in AMPA-subtype glutamate receptors.” Nature, 549: 60-65 (2017). PMID: 28737760.”
Twomey, E.C., Yelshanskaya, M.V., Grassucci, R.A., Frank, J., Sobolevsky, A.I. “Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes.” Neuron, 94: 569-580 (2017). PMID: 28472657.
Twomey, E.C., Yelshanskaya, M.V., Grassucci, R.A., Frank, J., Sobolevsky, A.I. “Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy.” Science, 353: 83-86 (2016). PMID: 27365450.