天冬酰胺 N-连接糖基化
中文名称
通路描述
N-连接糖基化是蛋白质在内质网合成和折叠过程中最重要的翻译后修饰形式（Stanley et al. 2009）。1999 年的一项早期研究表明，当时瑞士 -Prot 数据库中约 50% 的蛋白质已进行 N-糖基化（Apweiler et al. 1999）。现已确立，分泌途径中的大多数蛋白质需要糖基化才能实现正确的折叠。
向蛋白质添加 N-糖基可具有多种作用（Shental-Bechor & Levy 2009）。首先，糖基能增强蛋白质在内质网、高尔基体以及细胞膜外部的溶解性和稳定性，而该区域介质呈强亲水性，且蛋白质大多疏水，因此难以正确折叠。其次，N-糖基在蛋白质的折叠和运输过程中作为信号分子发挥作用：它们充当标签，以确定蛋白质何时需要与伴侣蛋白相互作用、被运输至高尔基体，或在发生严重折叠缺陷时靶向降解。第三，最重要的是，完全折叠的蛋白质上的 N-糖基参与广泛的生物学过程：它们帮助确定先天免疫或细胞间相互作用中膜受体的特异性，可以改变激素和分泌蛋白或细胞内囊泡系统中的蛋白质的性质。
所有 N-连接糖基均源自在内质网中合成的共同 14 糖寡糖前体，该前体在蛋白质翻译的同时通过寡糖转移酶（OST）共翻译地附着到蛋白质上。该糖基合成的过程被称为 N-糖基前体合成或 LLO，是真核生物中最保守的通路之一，也在某些细菌中被观察到。该附着通常发生在共识序列中的天冬酰胺残基上，由称为寡糖转移酶（OST）的复合物完成。
在附着到未折叠蛋白质后，糖基被用作折叠过程中的标签分子（也称为 Calnexin/Calreticulin 循环）（Lederkremer 2009）。内质网中大多数糖蛋白至少需要有一个糖基化残基才能实现正确折叠，尽管已证明内质网中部分蛋白质可以不经过此修饰即可折叠。
一旦糖蛋白实现正确折叠，它将通过顺式高尔基体穿过所有高尔基体隔室，在此过程中糖基根据糖蛋白的性质进一步修饰。该过程涉及相对较少的酶，但由于其组合性质，可能导致数百万种不同的可能修饰。该反应网络的确切拓扑结构尚未确立，这是人类基因组测序之后面临的主要挑战之一（Hossler et al. 2006）。
由于 N-糖基化涉及从细胞间相互作用到折叠控制的大量不同过程，参与糖基组装和/或修饰的基因突变可导致严重的发展问题（往往影响中枢神经系统）。所有涉及糖基化的疾病统称为先天性糖基化缺陷症（CDG）（Sparks et al. 2003），其中 LLO 合成途径的基因导致的疾病被分类为 CDG 类型 I，而其他基因导致的疾病被分类为 CDG 类型 II。
向蛋白质添加 N-糖基可具有多种作用（Shental-Bechor & Levy 2009）。首先，糖基能增强蛋白质在内质网、高尔基体以及细胞膜外部的溶解性和稳定性，而该区域介质呈强亲水性，且蛋白质大多疏水，因此难以正确折叠。其次，N-糖基在蛋白质的折叠和运输过程中作为信号分子发挥作用：它们充当标签，以确定蛋白质何时需要与伴侣蛋白相互作用、被运输至高尔基体，或在发生严重折叠缺陷时靶向降解。第三，最重要的是，完全折叠的蛋白质上的 N-糖基参与广泛的生物学过程：它们帮助确定先天免疫或细胞间相互作用中膜受体的特异性，可以改变激素和分泌蛋白或细胞内囊泡系统中的蛋白质的性质。
所有 N-连接糖基均源自在内质网中合成的共同 14 糖寡糖前体，该前体在蛋白质翻译的同时通过寡糖转移酶（OST）共翻译地附着到蛋白质上。该糖基合成的过程被称为 N-糖基前体合成或 LLO，是真核生物中最保守的通路之一，也在某些细菌中被观察到。该附着通常发生在共识序列中的天冬酰胺残基上，由称为寡糖转移酶（OST）的复合物完成。
在附着到未折叠蛋白质后，糖基被用作折叠过程中的标签分子（也称为 Calnexin/Calreticulin 循环）（Lederkremer 2009）。内质网中大多数糖蛋白至少需要有一个糖基化残基才能实现正确折叠，尽管已证明内质网中部分蛋白质可以不经过此修饰即可折叠。
一旦糖蛋白实现正确折叠，它将通过顺式高尔基体穿过所有高尔基体隔室，在此过程中糖基根据糖蛋白的性质进一步修饰。该过程涉及相对较少的酶，但由于其组合性质，可能导致数百万种不同的可能修饰。该反应网络的确切拓扑结构尚未确立，这是人类基因组测序之后面临的主要挑战之一（Hossler et al. 2006）。
由于 N-糖基化涉及从细胞间相互作用到折叠控制的大量不同过程，参与糖基组装和/或修饰的基因突变可导致严重的发展问题（往往影响中枢神经系统）。所有涉及糖基化的疾病统称为先天性糖基化缺陷症（CDG）（Sparks et al. 2003），其中 LLO 合成途径的基因导致的疾病被分类为 CDG 类型 I，而其他基因导致的疾病被分类为 CDG 类型 II。
英文描述
Asparagine N-linked glycosylation N-linked glycosylation is the most important form of post-translational modification for proteins synthesized and folded in the Endoplasmic Reticulum (Stanley et al. 2009). An early study in 1999 revealed that about 50% of the proteins in the Swiss-Prot database at the time were N-glycosylated (Apweiler et al. 1999). It is now established that the majority of the proteins in the secretory pathway require glycosylation in order to achieve proper folding.
The addition of an N-glycan to a protein can have several roles (Shental-Bechor & Levy 2009). First, glycans enhance the solubility and stability of the proteins in the ER, the golgi and on the outside of the cell membrane, where the composition of the medium is strongly hydrophilic and where proteins, that are mostly hydrophobic, have difficulty folding properly. Second, N-glycans are used as signal molecules during the folding and transport process of the protein: they have the role of labels to determine when a protein must interact with a chaperon, be transported to the golgi, or targeted for degradation in case of major folding defects. Third, and most importantly, N-glycans on completely folded proteins are involved in a wide range of processes: they help determine the specificity of membrane receptors in innate immunity or in cell-to-cell interactions, they can change the properties of hormones and secreted proteins, or of the proteins in the vesicular system inside the cell.
All N-linked glycans are derived from a common 14-sugar oligosaccharide synthesized in the ER, which is attached co-translationally to a protein while this is being translated inside the reticulum. The process of the synthesis of this glycan, known as Synthesis of the N-glycan precursor or LLO, constitutes one of the most conserved pathways in eukaryotes, and has been also observed in some eubacteria. The attachment usually happens on an asparagine residue within the consensus sequence asparagine-X-threonine by an complex called oligosaccharyl transferase (OST).
After being attached to an unfolded protein, the glycan is used as a label molecule in the folding process (also known as Calnexin/Calreticulin cycle) (Lederkremer 2009). The majority of the glycoproteins in the ER require at least one glycosylated residue in order to achieve proper folding, even if it has been shown that a smaller portion of the proteins in the ER can be folded without this modification.
Once the glycoprotein has achieved proper folding, it is transported via the cis-Golgi through all the Golgi compartments, where the glycan is further modified according to the properties of the glycoprotein. This process involves relatively few enzymes but due to its combinatorial nature, can lead to several millions of different possible modifications. The exact topography of this network of reactions has not been established yet, representing one of the major challenges after the sequencing of the human genome (Hossler et al. 2006).
Since N-glycosylation is involved in an great number of different processes, from cell-cell interaction to folding control, mutations in one of the genes involved in glycan assembly and/or modification can lead to severe development problems (often affecting the central nervous system). All the diseases in genes involved in glycosylation are collectively known as Congenital Disorders of Glycosylation (CDG) (Sparks et al. 2003), and classified as CDG type I for the genes in the LLO synthesis pathway, and CDG type II for the others.
The addition of an N-glycan to a protein can have several roles (Shental-Bechor & Levy 2009). First, glycans enhance the solubility and stability of the proteins in the ER, the golgi and on the outside of the cell membrane, where the composition of the medium is strongly hydrophilic and where proteins, that are mostly hydrophobic, have difficulty folding properly. Second, N-glycans are used as signal molecules during the folding and transport process of the protein: they have the role of labels to determine when a protein must interact with a chaperon, be transported to the golgi, or targeted for degradation in case of major folding defects. Third, and most importantly, N-glycans on completely folded proteins are involved in a wide range of processes: they help determine the specificity of membrane receptors in innate immunity or in cell-to-cell interactions, they can change the properties of hormones and secreted proteins, or of the proteins in the vesicular system inside the cell.
All N-linked glycans are derived from a common 14-sugar oligosaccharide synthesized in the ER, which is attached co-translationally to a protein while this is being translated inside the reticulum. The process of the synthesis of this glycan, known as Synthesis of the N-glycan precursor or LLO, constitutes one of the most conserved pathways in eukaryotes, and has been also observed in some eubacteria. The attachment usually happens on an asparagine residue within the consensus sequence asparagine-X-threonine by an complex called oligosaccharyl transferase (OST).
After being attached to an unfolded protein, the glycan is used as a label molecule in the folding process (also known as Calnexin/Calreticulin cycle) (Lederkremer 2009). The majority of the glycoproteins in the ER require at least one glycosylated residue in order to achieve proper folding, even if it has been shown that a smaller portion of the proteins in the ER can be folded without this modification.
Once the glycoprotein has achieved proper folding, it is transported via the cis-Golgi through all the Golgi compartments, where the glycan is further modified according to the properties of the glycoprotein. This process involves relatively few enzymes but due to its combinatorial nature, can lead to several millions of different possible modifications. The exact topography of this network of reactions has not been established yet, representing one of the major challenges after the sequencing of the human genome (Hossler et al. 2006).
Since N-glycosylation is involved in an great number of different processes, from cell-cell interaction to folding control, mutations in one of the genes involved in glycan assembly and/or modification can lead to severe development problems (often affecting the central nervous system). All the diseases in genes involved in glycosylation are collectively known as Congenital Disorders of Glycosylation (CDG) (Sparks et al. 2003), and classified as CDG type I for the genes in the LLO synthesis pathway, and CDG type II for the others.
所含基因
14 个基因