Tyrosinase and glycoprotein folding: Roles of chaperones that recognize glycans
Tyrosinase and glycoprotein folding: Roles of chaperones that recognize glycans
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DOI：
10.1021/bi000107z
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发表时间：
2000-05-09
期刊：
影响因子：
2.9
通讯作者：
Dwek, RA
中科院分区：
文献类型：
--
作者：
Petrescu, SM;Branza-Nichita, N;Dwek, RA
糖蛋白折叠在ER中通过多种机制调节，这些机制注定使多肽链能够获得天然糖蛋白的独特3D结构。人们普遍认为，折叠的效率取决于折叠多肽与ER驻留分子伴侣的相互作用。当然，ER分子伴侣之间存在明显的差异，这些差异可以用对新生多肽链暴露的识别元件的特异性来描述。尽管大多数分子伴侣识别多肽部分中的区域，但已知两种分子伴侣，钙连接蛋白和钙网蛋白，通过其与连接的N-聚糖的相互作用来调节新生链的折叠。钙连接蛋白/钙网蛋白与新生糖蛋白的相互作用是由N-聚糖加工早期阶段每个糖蛋白携带的单糖基化N-聚糖介导的。凝集素样相互作用促进有效折叠的重要发现为糖生物学提供了理解糖蛋白功能中N-糖基化作用的基本概念。最引人注目的是，早期N-聚糖加工阶段与新生多肽的分子伴侣介导的折叠有关，因此有助于ER中的质量控制机制。许多研究已经使用体外翻译系统来突出分子伴侣钙连接蛋白和钙网蛋白与新合成的糖蛋白之间的特异性相互作用（1，2）。这些糖蛋白依赖于它们与ER凝集素在从ER输出的能力和对降解的抗性方面的相互作用（3，4）。因此，从ER的输出被认为是分泌蛋白已达到其天然状态的指示（5）。当我们在体内系统中寻找确认时，这个概念是如何成立的？最近使用小鼠黑色素瘤酪氨酸酶的体内研究表明，尽管酪氨酸酶活性和折叠绝对依赖于与钙连接蛋白的相互作用，但绕过该质量控制并不会损害糖蛋白的细胞内转运（6，7）。由此可以得出两个重要的观点。首先，已经证实钙连接蛋白/钙网蛋白与新生糖蛋白链的结合对于体内正确折叠是至关重要的，如体外系统所示。第二，似乎出口能力概念可能不适用于所有蛋白质，特别是金属糖蛋白，如酪氨酸酶。
Glycoprotein folding is regulated in the ER by multiple mechanisms destined to enable the polypeptide chain to acquire the unique 3D structure of the native glycoprotein. It is widely held that the efficiency of the folding depends on the interaction of the folding polypeptide with ER-resident molecular chaperones. There certainly are distinct differences among the ER chaperones that can be described in terms of specificity toward the recognition elements exposed by the nascent polypeptide chain. Whereas most of the chaperones identify regions in the polypeptide moiety, two chaperones, calnexin and calreticulin, are known to modulate the folding of the nascent chain through their interaction with the attached N-glycans. Calnexin/calreticulin interaction with the nascent glycoprotein is mediated by the monoglucosylated N-glycans carried by every single glycoprotein in the early stages of the N-glycan processing. The important finding that a lectin-like interaction promotes efficient folding provides glycobiology with a fundamental concept for understanding the roles of N-glycosylation in glycoprotein function. Most strikingly, the early N-glycan processing stages are related to the chaperone-mediated folding of the nascent polypeptide, thus contributing to the quality control mechanism in the ER.A number of studies have used in vitro translation systems to highlight specific interactions between the chaperones calnexin and calreticulin and the newly synthesized glycoproteins (1, 2). These glycoproteins depend on their interaction with the ER lectins in terms of competence for export from the ER and resistance to degradation (3, 4). Therefore, export from the ER is taken as an indication of secretory proteins having reached their native state (5). How does this concept stand up when we look for confirmation in in vivo systems? Recent in vivo studies using mouse melanoma tyrosinase show that although tyrosinase activity and folding are absolutely dependent on the interaction with calnexin, the bypass of this quality control does not impair the intracellular transport of the glycoprotein (6, 7). Two important points follow from this. First, there is the confirmation that calnexin/calreticulin association with the nascent glycoprotein chain is crucial for the correct folding in vivo, as has been shown for in vitro systems. Second, it appears that the export competence concept might not apply to all proteins and in particular to metalloglycoproteins such as tyrosinase.