With the rapid expansion of sequencing of genomes, the functional annotation of proteins becomes a bottleneck in understanding proteomes. The Chromosome-centric Human Proteome Project (C-HPP) aims to identify all proteins encoded by the human genome and find functional annotations for them. However, until now there are still 1137 identified human proteins without functional annotation, called uPE1 proteins. Sequence alignment was insufficient to predict their functions, and the crystal structures of most proteins were unavailable. In this study, we demonstrated a new functional annotation strategy, AlphaFun, based on structural alignment using deep-learning-predicted protein structures. Using this strategy, we functionally annotated 99% of the human proteome, including the uPE1 proteins and missing proteins, which have not been identified yet. The accuracy of the functional annotations was validated using the known-function proteins. The uPE1 proteins shared similar functions to the known-function PE1 proteins and tend to express only in very limited tissues. They are evolutionally young genes and thus should conduct functions only in specific tissues and conditions, limiting their occurrence in commonly studied biological models. Such functional annotations provide hints for functional investigations on the uPE1 proteins. This proteome-wide-scale functional annotation strategy is also applicable to any other species.

中文翻译：

---

AlphaFun：基于结构比对的蛋白质组注释揭示了功能未知蛋白质 (uPE1) 为何未被充分研究

随着基因组测序的迅速扩展，蛋白质的功能注释成为理解蛋白质组的瓶颈。以染色体为中心的人类蛋白质组计划（C-HPP）旨在识别人类基因组编码的所有蛋白质并找到它们的功能注释。然而，到目前为止，仍有 1137 个已鉴定的人类蛋白质没有功能注释，称为 uPE1 蛋白质。序列比对不足以预测它们的功能，并且大多数蛋白质的晶体结构无法获得。在这项研究中，我们展示了一种新的功能注释策略 AlphaFun，该策略基于使用深度学习预测的蛋白质结构进行结构比对。使用这种策略，我们对 99% 的人类蛋白质组进行了功能注释，包括 uPE1 蛋白和尚未鉴定的缺失蛋白。使用已知功能的蛋白质验证功能注释的准确性。 uPE1 蛋白与已知功能的 PE1 蛋白具有相似的功能，并且往往仅在非常有限的组织中表达。它们是进化上年轻的基因，因此只能在特定的组织和条件下发挥作用，从而限制了它们在常用研究的生物模型中的出现。这种功能注释为 uPE1 蛋白的功能研究提供了线索。这种蛋白质组范围的功能注释策略也适用于任何其他物种。