biostudies-literaturePan HNational Key Research and Development Program of China1593-1602https://www.ebi.ac.uk/biostudies/studies/S-EPMC11078154biostudies-literatureUnknown23(5)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 anJournal of proteome researchAlphaFun: Structural-Alignment-Based Proteome Annotation Reveals why the Functionally Unknown Proteins (uPE1) Are So Understudied.PMC110781542023YFA0915800Pan HZhang GWu ZLiu WfalseAlphaFun: Structural-Alignment-Based Proteome Annotation Reveals why the Functionally Unknown Proteins (uPE1) Are So Understudied.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 an2024-01-01T00:00:00Z2024 May2026-04-08T19:50:26.834Z2025-06-26T03:06:07.466ZS-EPMC110781543862639210.1021/acs.jproteome.3c00678