Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nat Commun. 2017 Mar 28;8:14954. doi: 10.1038/ncomms14954.
HIV-1 envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs) and the focus for design of an antibody-based HIV vaccine. The Env trimer is covered by ∼90N-linked glycans, which shield the underlying protein from immune surveillance. bNAbs to HIV develop during infection, with many showing dependence on glycans for binding to Env. The ability to routinely assess the glycan type at each glycosylation site may facilitate design of improved vaccine candidates. Here we present a general mass spectrometry-based proteomics strategy that uses specific endoglycosidases to introduce mass signatures that distinguish peptide glycosites that are unoccupied or occupied by high-mannose/hybrid or complex-type glycans. The method yields >95% sequence coverage for Env, provides semi-quantitative analysis of the glycosylation status at each glycosite. We find that most glycosites in recombinant Env trimers are fully occupied by glycans, varying in the proportion of high-mannose/hybrid and complex-type glycans.
HIV-1 包膜糖蛋白(Env)是广泛中和抗体(bnAbs)的唯一靶标,也是基于抗体的 HIV 疫苗设计的重点。Env 三聚体被约 90 个 N-连接聚糖覆盖,这些聚糖使潜在的蛋白质免受免疫监视。在感染过程中会产生针对 HIV 的 bnAbs,其中许多 bnAbs 的结合依赖于聚糖与 Env 的结合。常规评估每个糖基化位点的聚糖类型的能力可能有助于设计改进的候选疫苗。在这里,我们提出了一种基于质谱的通用蛋白质组学策略,该策略使用特定的内切糖苷酶引入质量标记,以区分未被高甘露糖/杂合或复杂型聚糖占据或被其占据的肽糖基化位点。该方法对 Env 的覆盖率超过 95%,可对半定量分析每个糖基化位点的糖基化状态。我们发现重组 Env 三聚体中的大多数糖基化位点都被聚糖完全占据,其中高甘露糖/杂合和复杂型聚糖的比例有所不同。
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