Protein Components of the Synaptic Adhesive Scaffold

突触粘附支架的蛋白质成分

基本信息

批准号：
6896374
负责人：
DAVID R COLMAN
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-15 至 2007-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6896374
关键词：
brain cell adhesion molecules cell aggregation intermolecular interaction laboratory mouse mass spectrometry membrane reconstitution /synthesis protein localization protein structure function synapses yeast two hybrid system

项目摘要

Description (Provided by applicant): In the most contemporary view, the central nervous System synapse may be thought of as comprising 2 discrete subdomains which overlap structurally and functionally. The first domain is the synaptic "scaffold" which is observed by electron microscopy, consisting of apposed, rigorously parallel presynaptic and postsynaptic plasma membrane thickenings bound together by "crossbridges" that span the synaptic cleft. The scaffold is retained even after vigorous fractionation and detergent extraction of synaptosomes, and it seems clear that it is held together by adhesion molecules, whose identities remain unknown at present. The second subdomain is the neurotransmissional machinery through which the synapse mediates its primary physiological functions. This subdomain is superimposed upon the scaffold and interacts with it via molecular forces we don't understand as yet. Much effort has been focused on analyzing the physiological components of the synapse; however, the major constituents of the scaffold and how its intercellular adhesive components interact have remained elusive. This is because of inadequate fractionation techniques for the purification of intact CNS synaptic junctions, and the bewildering array of candidate proteins that may operate at different synapses. It is clear that efforts to recognize and evaluate changes in synaptic proteins which occur during degenerative processes must rely first on a complete catalog of the structural proteins involved in synaptic development and maintenance and how they interact with each other; and second, on an understanding of the intracellular binding partners for these scaffolding molecules which function in synaptic signaling phenomena, and in attachment to the underlying subsynaptic components. Long range, we want to understand exactly how molecular adhesive forces organize and stabilize the pre-to post-synaptic scaffold of the synaptic junctional complex in the CNS. We propose to: I) use a novel cell fractionation procedure we devised to purify synaptic junctional complexes in high yield, and then use newly developed methods in mass spectrometry to identify the component adhesion and adhesion associated molecules, and II) begin studies on the interactions between these molecules which lead to the assembly of the synaptic junctional complex in the CNS.

描述（由申请人提供）：在最现代的角度，中央神经系统突触可能被认为是2个离散子域在结构和功能上重叠。第一个域是突触 “脚手架”，通过电子显微镜观察到，由供应，严格平行的突触前和突触后质膜增厚由跨越突触裂缝的“杂交桥”结合在一起。脚手架是即使在剧烈分馏和清洁剂提取后仍保留突触体，似乎很明显它是通过粘附固定在一起的分子，其身份目前尚不清楚。第二个子域是神经递质机械通过，突触使其介导主要的生理功能。这个子域被叠加在脚手架并通过我们尚不理解的分子力与之相互作用。大量精力集中在分析的生理组成部分上突触；但是，脚手架的主要成分以及如何细胞间粘合剂组件相互作用仍然难以捉摸。这是由于无法纯化的分馏技术不足中枢神经系统的突触连接，以及令人困惑的候选蛋白质阵列可以在不同的突触中运行。显然，认识和评估在退化过程中发生的突触蛋白的变化必须首先依靠涉及的结构蛋白的完整目录突触开发和维护以及它们如何相互作用；和第二，了解这些细胞内结合伙伴在突触信号现象中起作用的脚手架分子，在附着在基础次突触成分上。远距离，我们想准确了解分子粘合力如何组织和稳定突触的前突触后支架中枢神经系统中的连接综合体。我们建议：i）使用新颖的细胞分馏我们设计的程序是为了纯化高产量的突触连接络合物，并且然后使用新开发的质谱方法来识别组件粘附和粘附相关的分子，ii）开始研究这些分子之间的相互作用，导致突触的组装中枢神经系统中的连接综合体。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamics of presynaptic protein recruitment induced by local presentation of artificial adhesive contacts.

DOI：
10.1002/dneu.22037
发表时间：
2013-01
期刊：
DEVELOPMENTAL NEUROBIOLOGY
影响因子：
3
作者：
Suarez, Fernando;Thostrup, Peter;Colman, David;Grutter, Peter
通讯作者：
Grutter, Peter

N-cadherin prodomain cleavage regulates synapse formation in vivo.

DOI：
10.1002/dneu.20718
发表时间：
2009-07
期刊：
DEVELOPMENTAL NEUROBIOLOGY
影响因子：
3
作者：
Latefi, Nazlie S.;Pedraza, Lifiana;Schohl, Anne;Li, Ziwei;Ruthazer, Edward S.
通讯作者：
Ruthazer, Edward S.

Structural stabilization of CNS synapses during postnatal development in rat cortex.

大鼠皮层出生后发育过程中中枢神经系统突触的结构稳定性。