Format

Send to

Choose Destination
Biol Direct. 2015 Jul 31;10:38. doi: 10.1186/s13062-015-0069-2.

De-DUFing the DUFs: Deciphering distant evolutionary relationships of Domains of Unknown Function using sensitive homology detection methods.

Author information

1
IISc Mathematics Initiative, Indian Institute of Science, Bangalore, 560 012, India. rmudgal@mbu.iisc.ernet.in.
2
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560 012, India. sandhya@mbu.iisc.ernet.in.
3
Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India. nchandra@biochem.iisc.ernet.in.
4
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560 012, India. ns@mbu.iisc.ernet.in.

Abstract

BACKGROUND:

In the post-genomic era where sequences are being determined at a rapid rate, we are highly reliant on computational methods for their tentative biochemical characterization. The Pfam database currently contains 3,786 families corresponding to "Domains of Unknown Function" (DUF) or "Uncharacterized Protein Family" (UPF), of which 3,087 families have no reported three-dimensional structure, constituting almost one-fourth of the known protein families in search for both structure and function.

RESULTS:

We applied a 'computational structural genomics' approach using five state-of-the-art remote similarity detection methods to detect the relationship between uncharacterized DUFs and domain families of known structures. The association with a structural domain family could serve as a start point in elucidating the function of a DUF. Amongst these five methods, searches in SCOP-NrichD database have been applied for the first time. Predictions were classified into high, medium and low- confidence based on the consensus of results from various approaches and also annotated with enzyme and Gene ontology terms. 614 uncharacterized DUFs could be associated with a known structural domain, of which high confidence predictions, involving at least four methods, were made for 54 families. These structure-function relationships for the 614 DUF families can be accessed on-line at http://proline.biochem.iisc.ernet.in/RHD_DUFS/ . For potential enzymes in this set, we assessed their compatibility with the associated fold and performed detailed structural and functional annotation by examining alignments and extent of conservation of functional residues. Detailed discussion is provided for interesting assignments for DUF3050, DUF1636, DUF1572, DUF2092 and DUF659.

CONCLUSIONS:

This study provides insights into the structure and potential function for nearly 20 % of the DUFs. Use of different computational approaches enables us to reliably recognize distant relationships, especially when they converge to a common assignment because the methods are often complementary. We observe that while pointers to the structural domain can offer the right clues to the function of a protein, recognition of its precise functional role is still 'non-trivial' with many DUF domains conserving only some of the critical residues. It is not clear whether these are functional vestiges or instances involving alternate substrates and interacting partners.

PMID:
26228684
PMCID:
PMC4520260
DOI:
10.1186/s13062-015-0069-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center