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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）：在最现代的观点中，中央神经系统突触可以被认为包含 2 个离散的子域它们在结构和功能上重叠。第一个域是突触通过电子显微镜观察到的“支架”，由并置的、严格平行的突触前和突触后质膜增厚通过跨越突触间隙的“横桥”连接在一起。脚手架是即使经过剧烈分馏和洗涤剂萃取后仍保留突触体，而且很明显它是通过粘附力结合在一起的分子，其身份目前仍未知。第二个子域是突触通过其介导其神经传递机制主要生理功能。该子域叠加在支架并通过我们尚不了解的分子力与其相互作用。人们付出了很多努力来分析其生理成分突触；然而，支架的主要成分及其如何细胞间粘附成分的相互作用仍然难以捉摸。这是由于分馏技术不足以纯化完整的中枢神经系统突触连接，以及一系列令人眼花缭乱的候选蛋白质可以在不同的突触上运作。显然，努力认识和评估退化过程中发生的突触蛋白的变化必须首先依赖于所涉及的结构蛋白的完整目录突触的发育和维持以及它们如何相互作用；和其次，了解这些的细胞内结合伙伴在突触信号现象中发挥作用的支架分子附着到下面的突触亚组件。长距离，我们想要准确地了解分子粘合力是如何产生的组织和稳定突触的突触前至突触后支架中枢神经系统中的连接复合体。我们建议：I) 使用新型细胞分级分离我们设计的程序以高产率纯化突触连接复合物，并且然后使用新开发的质谱方法来识别成分粘附和粘附相关分子，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复合体。

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。