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The Journal of Neuroscience, October 7, 2009, 29(40):12584-12596; doi:10.1523/JNEUROSCI.1255-09.2009

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Cellular/Molecular
A Protein Interaction Node at the Neurotransmitter Release Site: Domains of Aczonin/Piccolo, Bassoon, CAST, and Rim Converge on the N-Terminal Domain of Munc13-1

Xiaolu Wang,¹ Bin Hu,¹ Agata Zieba,² Nicole G. Neumann,² Monika Kasper-Sonnenberg,¹ Annegret Honsbein,² Greta Hultqvist,² Tim Conze,^1,2 Wolfgang Witt,¹ Christoph Limbach,² Matthis Geitmann,³ Helena Danielson,³ Richard Kolarow,⁴ Gesa Niemann,⁴ Volkmar Lessmann,^4,5 and Manfred W. Kilimann^1,2

¹Institut für Physiologische Chemie, Ruhr-Universität Bochum, D-44780 Bochum, Germany, Departments of ²Neuroscience and ³Biochemistry and Organic Chemistry, Uppsala University, S-75124 Uppsala, Sweden, ⁴Institute for Physiology, University of Mainz, D-55128 Mainz, Germany, and ⁵Institute of Physiology, Otto-von-Guericke University, D-39120 Magdeburg, Germany

Correspondence should be addressed to Manfred W. Kilimann, Department of Neuroscience, Box 593, Uppsala University, S-75124 Uppsala, Sweden. Email: manfred.kilimann{at}neuro.uu.se

Multidomain scaffolding proteins organize the molecular machinery of neurotransmitter vesicle dynamics during synaptogenesis and synaptic activity. We find that domains of five active zone proteins converge on an interaction node that centers on the N-terminal region of Munc13-1 and includes the zinc-finger domain of Rim1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the third coiled-coil domain (CC3) of either Aczonin/Piccolo or Bassoon. This multidomain complex may constitute a center for the physical and functional integration of the protein machinery at the active zone. An additional connection between Aczonin and Bassoon is mediated by the second coiled-coil domain of Aczonin. Recombinant Aczonin-CC3, expressed in cultured neurons as a green fluorescent protein fusion protein, is targeted to synapses and suppresses vesicle turnover, suggesting involvements in synaptic assembly as well as activity. Our findings show that Aczonin, Bassoon, CAST1, Munc13, and Rim are closely and multiply interconnected, they indicate that Aczonin-CC3 can actively participate in neurotransmitter vesicle dynamics, and they highlight the N-terminal region of Munc13-1 as a hub of protein interactions by adding three new binding partners to its mechanistic potential in the control of synaptic vesicle priming.

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Received March 8, 2009; revised Aug. 19, 2009; accepted Aug. 21, 2009.

Correspondence should be addressed to Manfred W. Kilimann, Department of Neuroscience, Box 593, Uppsala University, S-75124 Uppsala, Sweden. Email: manfred.kilimann{at}neuro.uu.se

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