The human cis-prenyltransferase complex (hcis-PT) is an enzymatic complex essential for protein N-glycosylation. Synthesizing the precursor for the glycosyl carrier dolichol-phosphate, hcis-PT was previously associated with various congenital glycosylation disorders. Here, we reveal that hcis-PT exhibits a novel heterotetrameric assembly in solution, composed of two catalytic dehydrodolichyl diphosphate synthase (DHDDS) and two inactive Nogo-B receptor (NgBR) subunits. The 2.3 Å crystal structure of the complex exposes a dimer-of-heterodimers arrangement, with DHDDS C-termini serving as homotypic assembly domains. Furthermore, the structure elucidates the molecular details associated with substrate binding, catalysis and product length determination. Importantly, the distal C-terminus of NgBR transverses across the heterodimeric interface, directly participating in substrate binding and underlying the allosteric communication between the subunits. Finally, mapping disease-associated mutations onto the structure reveals their clustering around the active site. Together, our structure of the hcis-PT complex unveils the mechanisms involved in dolichol synthesis in health and disease.

中文翻译：

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人异四聚体顺-异戊二烯基转移酶复合物的结构

人的顺式异戊二烯基转移酶复合物（hcis-PT）是蛋白质N-糖基化必不可少的酶复合物。hcis-PT合成糖基载体多羟基磷酸酯的前体，以前与各种先天性糖基化疾病有关。在这里，我们揭示了hcis-PT在溶液中表现出一种新颖的异四聚体组装，由两个催化的脱氢二氢二磷酸二磷酸合酶（DHDDS）和两个无活性的Nogo-B受体（NgBR）亚基组成。该复合物的2.3Å晶体结构暴露出二聚体的异二聚体排列，DHDDS C末端用作同型装配结构域。此外，该结构阐明了与底物结合，催化和产物长度测定有关的分子细节。重要的是，NgBR的远端C末端横穿异二聚体界面，直接参与底物结合并成为亚基之间的变构通讯的基础。最后，将与疾病相关的突变映射到结构上可以揭示它们围绕活性位点的聚集。在一起，我们的hcis-PT复合物的结构揭示了健康和疾病中参与多氢酚合成的机制。