Physiological relevance and dynamic regulation of APLP-mediated cell:cell interactions

APLP 介导的细胞与细胞相互作用的生理相关性和动态调节

• 批准号: 163147043
• 负责人: Professor Dr. Gerhard Multhaup
• 金额: --
• 依托单位: Department of Pharmacology and Therapeutics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/163147043?language=en
• 关键词: Physiological; relevance; dynamic; regulation; APLP

The amyloid precursor protein (APP) and the homologous amyloid precursor-like proteins (APLPs) are members of an evolutionary conserved protein family. The current knowledge suggests key physiological functions for APLPs among family members. Recently, we have shown that APLP1 mainly localizes to the cell surface in contrast to APP and APLP2. Our newly discovered Zn-dependent generation of APLP1 mediated cell:cell contacts opens up new perspectives for the functional characterization of APP family proteins. Thus, the main goal of this project is to investigate the biochemical basis, the dynamics and the cell-biological relevance of APP and AP-like proteins (APLP1, APLP2) in forming cis-bridged homo- or heterooligomeric complexes and trans-interacting cell:cell contacts. Furthermore, we will investigate how α- or β-secretase cleavages affect cell:cell contacts mediated by cis- or cis/trans-interacting complexes. One challenge of the proposed project is the analysis of APP:APLP1 complex processing of covalently linked heterodimers of Aß and Aß-like peptides. This is expected to lead to the identification of the exact cleavage sites of Aß-like peptides derived from APLP1 and contribute to understand the functional role of APLPs in the AD pathogenesis.

淀粉样前体蛋白（APP）和同源淀粉样前体蛋白样蛋白（APLPs）是进化上保守的蛋白质家族成员。目前的知识表明，APLPs在家庭成员中具有关键的生理功能。最近，我们已经表明，APLP 1主要定位于细胞表面，而APP和APLP 2。我们新发现的锌依赖性APLP 1介导的细胞：细胞接触的产生为APP家族蛋白的功能表征开辟了新的前景。因此，本项目的主要目标是研究APP和AP样蛋白（APLP 1，APLP 2）在形成顺式桥接同源或异源寡聚复合物和反式相互作用细胞：细胞接触中的生物化学基础，动力学和细胞生物学相关性。此外，我们将研究α-或β-分泌酶切割如何影响细胞：细胞接触介导的顺式或顺式/反式相互作用的复合物。所提出的项目的一个挑战是分析APP：APLP 1复合物对共价连接的AAPs和AAPs样肽的异二聚体的加工。这有望导致鉴定源自APLP 1的APLPs样肽的确切切割位点，并有助于理解APLPs在AD发病机制中的功能作用。