title: Unexpected features of the dark proteome.
abstract: We surveyed the "dark" proteome-that is, regions of proteins never observed by experimental structure determination and inaccessible to homology modeling. For 546,000 Swiss-Prot proteins, we found that 44-54% of the proteome in eukaryotes and viruses was dark, compared with only ∼14% in archaea and bacteria. Surprisingly, most of the dark proteome could not be accounted for by conventional explanations, such as intrinsic disorder or transmembrane regions. Nearly half of the dark proteome comprised dark proteins, in which the entire sequence lacked similarity to any known structure. Dark proteins fulfill a wide variety of functions, but a subset showed distinct and largely unexpected features, such as association with secretion, specific tissues, the endoplasmic reticulum, disulfide bonding, and proteolytic cleavage. Dark proteins also had short sequence length, low evolutionary reuse, and few known interactions with other proteins. These results suggest new research directions in structural and computational biology.
authors.affiliation: Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal; Instituto de Sistemas e Robótica, 1049-001 Lisbon, Portugal;
authors.forename: Nelson
authors.initials: N
authors.lastname: Perdigão
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 1670, Australia;
authors.forename: Julian
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 1670, Australia;
authors.forename: Christian
authors.initials: C
authors.lastname: Stolte
authors.affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Information Technology, The University of Sydney, Sydney, NSW 2006, Australia;
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Sabir
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 1670, Australia;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buckley
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 1670, Australia;
authors.forename: Bruce
authors.initials: B
authors.lastname: Tabor
authors.affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
authors.forename: Beth
authors.initials: B
authors.lastname: Signal
authors.affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
authors.forename: Brian S
authors.initials: BS
authors.lastname: Gloss
authors.affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammang
authors.affiliation: Department for Bioinformatics and Computational Biology, Technische Universität München, 80333 Munich, Germany;
authors.forename: Burkhard
authors.initials: B
authors.lastname: Rost
authors.affiliation: Department for Bioinformatics and Computational Biology, Technische Universität München, 80333 Munich, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Schafferhans
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, NSW 1670, Australia; Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Molecular Bioscience, The University of Sydney, Sydney, NSW 2006, Australia sean@odonoghuelab.org.
authors.forename: Seán I
authors.identifier: http://orcid.org/0000-0001-9520-6623
authors.initials: SI
authors.lastname: O'Donoghue
mesh_terms: D000465:Algorithms; D000818:Animals; D001105:Archaea / Q000235:genetics / Q000378:metabolism; D001419:Bacteria / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D056890:Eukaryota / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014780:Viruses / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D020543:Proteome
keywords: protein disorder; secreted proteins; structure prediction; transmembrane proteins; unknown unknowns