Visualization of SV2A conformations in situ by the use of Protein Tomography.
The synaptic vesicle protein 2A (SV2A), the brain-binding site of the anti-epileptic drug levetiracetam (LEV), has been characterized by Protein Tomography. We identified two major conformations of SV2A in mouse brain tissue: first, a compact, funnel-structure with a pore-like opening towards the cytoplasm; second, a more open, V-shaped structure with a cleft-like opening towards the intravesicular space. The large differences between these conformations suggest a high degree of flexibility and support a valve-like mechanism consistent with the postulated transporter role of SV2A. These two conformations are represented both in samples treated with LEV, and in saline-treated samples, which indicates that LEV binding does not cause a large-scale conformational change of SV2A, or lock a specific conformational state of the protein. This study provides the first direct structural data on SV2A, and supports a transporter function suggested by sequence homology to MFS class of transporter proteins.
Lynch
Berkley A
BA
Department of Molecular and Cellular Sciences, UCB S.A., Granta Park, Great Abington, Cambridge, Cambridgeshire CB16GS, UK.
Matagne
Alain
A
Brännström
Annika
A
von Euler
Anne
A
Jansson
Magnus
M
Hauzenberger
Elenor
E
Söderhäll
J Arvid
JA
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology; D001923:Brain Chemistry; D007150:Immunohistochemistry / Q000379:methods; D000077287:Levetiracetam; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010889:Piracetam / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation
D000927:Anticonvulsants; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489614:Sv2a protein, mouse; D000077287:Levetiracetam; D010889:Piracetam