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The number of available protein sequences in public databases is increasing exponentially. However, a significant percentage of these sequences lack functional annotation, which is essential for the understanding of how biological systems operate. We propose a novel method, Quantitative Annotation of Unknown STructure (QAUST), to infer protein functions, specifically Gene Ontology (GO) terms and Enzyme Commission (EC) numbers. QAUST uses three sources of information: structure information encoded by global and local structure similarity search, biological network information inferred by protein–protein interaction data, and sequence information extracted from functionally discriminative sequence motifs. These three pieces of information are combined by consensus averaging to make the final prediction. Our approach has been tested on 500 protein targets from the CAFA (Critical Assessment of Functional Annotation) benchmark set. The results show that our method provides accurate functional annotation and outperforms other prediction methods based on sequence similarity search or threading. We further demonstrate that a previously unknown function of TRIM22 protein predicted by QAUST can be experimentally validated. QAUST can be accessed at http://www.cbrc.kaust.edu.sa/qaust/submit/.