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，提供了一系列生命必需的功能。所有这些组织的成分都是在我们体内特殊类型的细胞内制成的，然后将它们释放或分泌到细胞外，各个成分组装形成复杂的网络，最终生成特定组织的物理结构。分泌的成分通常是大蛋白质，在从细胞分泌之前和之后会经历广泛的修饰。分泌的蛋白质是在细胞内称为内质网的特定区室中合成的，其中许多蛋白质经过广泛的修饰，通常涉及在称为糖基化的过程中添加糖链。然后蛋白质被装在小球形包中运输到另一个称为高尔基体的隔室，在那里发生进一步的糖基化和对添加的糖链的加工。然后修饰的蛋白质在高尔基体中包装到不同的囊泡中，以递送到细胞表面并从细胞中释放。许多人类疾病都会影响皮肤和骨骼的形成或维护，而且众所周知，这两种组织都会随着人们年龄的增长而退化。一种被称为骨发育不良的罕见遗传性疾病会导致皮肤松弛、起皱和骨质疏松症，这些症状与衰老过程中出现的症状类似。 GO 的病因是编码高尔基体蛋白 GORAB 的基因突变。 GORAB 的功能尚不清楚，因此我们不了解 GO 症状是如何产生的。我们已经获得初步证据，表明 GORAB 对于高尔基复合体的囊泡运输以及正确处理通过该区室的货物蛋白上的糖链非常重要。因此，我们认为 GO 是由构成皮肤和骨骼的蛋白质修饰缺陷引起的，从而导致在这些组织中观察到的病理效应。这里描述的工作旨在确定 GORAB 在高尔基体囊泡运输中的精确功能，然后确定 GORAB 的丢失如何影响分泌蛋白的修饰，重点关注构成皮肤的蛋白。这项工作不仅对于确定 GO 的机制很重要，而且对于我们更广泛地理解货物修饰具有更广泛的意义，这对所有细胞都至关重要。此外，研究结果将告诉我们皮肤是如何组装的，以及皮肤在疾病和正常衰老过程中如何变化。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相关。

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