Dissecting the function of GORAB, the protein mutated in Geroderma osteodysplastica

剖析 GORAB 的功能，GORAB 是骨发育不良中突变的蛋白质

• 批准号: MR/N000366/1
• 负责人: Martin Lowe
• 金额: $ 51.51万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN000366%2F1
• 关键词: Dissecting; function; GORAB; protein; mutated

Skin, bone, cartilage and connective tissues in our body are clearly important, providing a range of functions that are essential for life. The components of all of these tissues are made inside special types of cells in our body, which then release, or secrete, them outside the cell, upon which the individual components assemble to form complex networks that ultimately generate the physical structure of the particular tissue. The secreted components are typically large proteins that undergo extensive modifications prior to and after their secretion from the cell. The secreted proteins are synthesized in a particular compartment inside the cell called the endoplasmic reticulum, where many undergo extensive modification, commonly involving the addition of linked chains of sugars in a process termed glycosylation. Proteins are then transported in small spherical packets to another compartment called the Golgi apparatus, where further glycosylation and processing of the added sugar chains occurs. The modified proteins are then packaged at the Golgi apparatus into different vesicles for delivery to the cell surface and release from the cell. Many human diseases affect the formation or maintenance of the skin and bones, and moreover, it is well known that both tissues degenerate as people get older. A rare genetic disorder called Geroderma osteodysplastica causes loose, wrinkly skin and osteoporosis, symptoms similar to those seen in ageing. The cause of GO is mutation of a gene that encodes for a Golgi apparatus protein called GORAB. The function of GORAB is not known, and consequently we do not understand how the symptoms of GO are brought about. We have obtained preliminary evidence that GORAB is important for vesicle transport at the Golgi complex and for the correct processing of sugar chains on cargo proteins transiting through this compartment. Hence, we propose that GO is caused by defective modification of proteins that make up the skin and bone, leading to the pathological effects that are observed in these tissues. The work described here aims to determine the precise function of GORAB in Golgi vesicle transport, and then to determine how the loss of GORAB affects modification of secreted proteins, focusing on those that make up the skin. The work will not only be important for determining the mechanisms of GO, but have more widespread significance for our understanding of cargo modification more generally, which is of fundamental importance to all cells. Moreover, the results will inform us of how the skin is assembled, and how the skin changes both in disease but also likely during the normal ageing process. Finally, the work also has relevance to our understanding of processes such as tissue regeneration and wound repair.

我们体内的皮肤，骨骼，软骨和结缔组织显然很重要，提供了一系列对生命必不可少的功能。所有这些组织的成分是在我们体内特殊类型的细胞内部制成的，然后将它们释放或分泌，将它们在细胞之外释放或分泌，在这些细胞中，各个组件在其上组装以形成复杂的网络，以最终产生特定组织的物理结构。分泌的成分通常是大型蛋白质，它们在分泌细胞之前和之后进行了广泛的修饰。分泌的蛋白质是在称为内质网的细胞内部特定隔室中合成的，其中许多经历了广泛的修饰，通常涉及在称为糖基化的过程中添加糖的连锁链。然后，将蛋白质在小球包中运输到另一个称为高尔基体设备的隔室，在此过程中，发生了进一步的糖基化和添加的糖链的加工。然后将修饰的蛋白质在高尔基体中包装到不同的囊泡中，以递送至细胞表面并从细胞中释放。许多人类疾病会影响皮肤和骨骼的形成或维持，而且众所周知，随着人们的年龄增长，两者都会退化。一种称为头皮骨质塑料的罕见遗传疾病会导致皮肤松动，骨质疏松症，症状与衰老中的症状相似。 GO的原因是一个基因的突变，该基因编码称为Gorab的高尔基体蛋白。 Gorab的功能尚不清楚，因此我们不了解GO的症状是如何带来的。我们已经获得了初步证据，表明gorab对于高尔基体复合物的囊泡转运很重要，以及在通过该隔室转移的货物蛋白上正确加工糖链。因此，我们认为GO是由构成皮肤和骨骼的蛋白质有缺陷引起的，从而导致在这些组织中观察到的病理作用。此处描述的工作旨在确定Gorab在高尔基体囊泡转运中的精确功能，然后确定gorab丢失如何影响分泌蛋白的修饰，重点关注那些构成皮肤的蛋白质。这项工作不仅对于确定GO机制很重要，而且对于我们对货物修饰的理解具有更广泛的意义，这对所有细胞至关重要。此外，结果将告知我们皮肤的组装方式，以及皮肤在疾病中的变化以及在正常衰老过程中的可能性。最后，这项工作还与我们对组织再生和伤口修复等过程的理解有关。

项目成果

The Golgin Family of Coiled-Coil Tethering Proteins.

• DOI: 10.3389/fcell.2015.00086
• 发表时间: 2015
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Witkos TM;Lowe M
• 通讯作者: Lowe M

Vimentin intermediate filaments provide structural stability to the mammalian Golgi complex.

• DOI: 10.1242/jcs.260577
• 发表时间: 2023-10-15
• 期刊: JOURNAL OF CELL SCIENCE
• 影响因子: 4
• 作者: Vitali, Teresa;Sanchez-Alvarez, Rosa;Witkos, Tomasz M.;Bantounas, Ioannis;Cutiongco, Marie F. A.;Dudek, Michal;Yan, Guanhua;Mironov, Alexander A.;Swift, Joe;Lowe, Martin
• 通讯作者: Lowe, Martin

A common pathomechanism in GMAP-210- and LBR-related diseases.

GMAP-210 和 LBR 相关疾病的常见病理机制。

• DOI: 10.1172/jci.insight.121150
• 发表时间: 2018
• 期刊: JCI insight
• 影响因子: 8
• 作者: Wehrle A