所長招聘セミナー

日 時 2012年05月31日 15:00~16:00
場 所 山手地区 3号館2階西 大会議室
演 者 杉田 修三 先生(University Health Network/University of Tronto, Canada)
演 題 Molecular insight into the mechanisms underlying the pleiotropic functions of Munc18-1 in exocytosis.
要 旨

Munc18-1 plays essential roles in neurosecretion through interaction with syntaxin as well as the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex. However, how these interactions contribute to critical functions of Munc18-1 remains unclear. At least three important functions of Munc18-1 have been proposed: (i) molecular chaperone of syntaxin-1 for appropriate localization and expression of syntaxin-1, (ii) priming/stimulation of the SNARE-mediated membrane fusion, and (iii) docking of large dense-core vesicles to the plasma membrane. Similarly, at least three different binding modes have been proposed for the interaction between Munc18-1 and syntaxin-1 or the SNARE complex: (i) binary interaction with a “closed” conformation of syntaxin-1, (ii) binding to the N-terminal peptide of syntaxin-1, and (iii) interaction with the assembled SNARE complex. Recent structural analyses have identified critical Munc18-1 residues implicated in these different modes of binding. Functional specificities of these residues have recently been tested by our group and others through rescue experiments using Munc18-1/-2 knockdown PC12 cells and Munc18-1 null neurons. Such approach has resulted in remarkable progress in the structural/functional understanding of Munc18-1. Our recent results indicate that the domain-1 cleft of Munc18-1 is essential for binding to the “closed” conformation of syntaxin-1 and thereby critical for its syntaxin-1 chaperoning, dense-core vesicle docking, and secretory functions. Moreover, our data suggests that interaction between Munc18-1 and syntaxin-1 N-terminal peptide is largely dispensable for its secretory function. In this seminar, I will propose an updated model of the pleiotropic functions of Munc18-1 in neuroexocytosis.

連絡先 田渕克彦 (内線:5279) 生理学研究所脳形態解析研究部門