INTRACELLULAR TRAFFICKING OF TROPOELASTIN

原弹性蛋白的细胞内运输

• 批准号: 6476867
• 负责人: FREDERICK GRINNELL
• 金额: $ 21.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476867
• 关键词: FK506; elastic tissue; elastin; extracellular matrix; intracellular transport; laboratory mouse; laboratory rabbit; molecular chaperones; peptidylprolyl isomerase; protein binding; protein folding; protein transport; recombinant proteins

Elastic fiber assembly is a complicated process that involves the organization of tropoelastin monomers on a microfibril scaffold and the subsequent crosslinking of these monomers into an insoluble elastin matrix. In the vessel wall, elastic fibers form concentric lamellae that are critical for the structural integrity and function of the vessel. Increasing evidence suggests that in virtually all vascular diseases, some aspect of elastic fiber assembly or structure is affected. Our ability to study these aberrant changes, however, is presently restricted by our limited knowledge of how elastic fibers normally assemble in developing tissues. Although significant advances have been made in the characterization of elastic fiber components, we know remarkably little about the intracellular events involved in their targeting and eventual secretion from the cell. Recently, we have shown that within the secretory pathway, tropoelastin is a ligand for a 65-kD FK506 binding protein (FKBP65). Since little is known about FKBP65, our first specific aim is to fully characterize the protein by determining its temporal and tissue specific distribution, establishing its intracellular location and topography, and identifying additional ligands for the protein. Since members of the FKBP family are peptidyl- prolyl cis-trans isomerases that have been implicated in folding and trafficking events, the association of tropoelastin with FKBP65 raises the intriguing hypothesis that FKBP65 plays a role in the folding and/or transport of tropoelastin to membrane assembly sites. Our second specific aim, therefore, is to test this hypothesis by studying the direct binding of tropoelastin to FKBP65 in in vitro assays, determining if FKBP65 has isomerization activity on tropoelastin-specific peptides, and investigating the role of FKBP65 in tropoelastin expression, secretion and assembly by treating cells with the immunosuppressant drug, FK506, to disrupt the FKBP65-tropoelastin interaction. In our third specific aim, we will extend our present studies on the intracellular trafficking of tropoelastin by identifying additional proteins and chaperones that associate with tropoelastin in the secretory pathway and by characterizing the post-Golgi transport of the protein based on our preliminary data that supports a role for an acidic compartment in the transport of tropoelastin to the cell surface. Results from these studies will not only provide fundamental information concerning the intracellular events required for normal elastic fiber assembly, but will ultimately establish an important basis for future studies on elastic fibers in a number of vascular diseases, such as supravalvular aortic stenosis, hypertension and aortic aneurysms.

弹性纤维的装配是一个复杂的过程

项目成果

Supravalvular aortic stenosis: genetic and molecular dissection of a complex mutation in the elastin gene.

瓣膜上主动脉瓣狭窄：弹性蛋白基因复杂突变的遗传和分子解剖。

• DOI: 10.1007/s00439-001-0608-z
• 发表时间: 2001
• 期刊: Human genetics.
• 作者: Urban,Z;Zhang,J;Davis,EC;Maeda,GK;Kumar,A;Stalker,H;Belmont,JW;Boyd,CD;Wallace,MR
• 通讯作者: Wallace,MR

Genomic organization of mouse and human 65 kDa FK506-binding protein genes and evolution of the FKBP multigene family.

• DOI: 10.1006/geno.2002.6777
• 发表时间: 2002-06
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Charles E. Patterson;Jimin Gao;A. Rooney;E. Davis