DUF

The Domain of Unknown Function (DUF) is a protein-domain classification used to designate conserved regions of protein sequences whose biological function has not yet been determined experimentally. The DUF label helps researchers organize sequence data and prevent premature or incorrect functional annotation. In practice, DUFs are defined by sequence similarity and are assigned numeric identifiers (for example, DUFXXXX) in databases such as Pfam and InterPro.

DUFs are found across all domains of life, including bacteria, archaea, and eukaryotes, and can vary in size from a few tens to several hundreds of amino acids. They often arise as modular components within multidomain proteins, where their presence can provide hints about protein architecture and potential interactions even when the precise role is unknown. Because DUFs are defined by conservation rather than function, many remain uncharacterized despite being widely distributed.

Characterization of DUFs proceeds through comparative genomics, structural biology, and computational prediction. Some DUF families eventually acquire functional annotations as new data become available, while others persist as unresolved domains. Structural determination or experimental assays can reveal enzymatic activity, ligand binding, or regulatory roles, leading to reclassification from DUF to a described domain.

DUF classifications are dynamic and subject to revision. A DUF label may be dropped once function is identified or reclassified if the domain is found to belong to an already characterized family. As placeholders for unknown biology, DUFs play a key role in guiding experimental prioritization and in documenting the evolving landscape of protein domains.