title: 3D profile-based approach to proteome-wide discovery of novel human chemokines.
abstract: Chemokines are small secreted proteins with important roles in immune responses. They consist of a conserved three-dimensional (3D) structure, so-called IL8-like chemokine fold, which is supported by disulfide bridges characteristic of this protein family. Sequence- and profile-based computational methods have been proficient in discovering novel chemokines by making use of their sequence-conserved cysteine patterns. However, it has been recently shown that some chemokines escaped annotation by these methods due to low sequence similarity to known chemokines and to different arrangement of cysteines in sequence and in 3D. Innovative methods overcoming the limitations of current techniques may allow the discovery of new remote homologs in the still functionally uncharacterized fraction of the human genome. We report a novel computational approach for proteome-wide identification of remote homologs of the chemokine family that uses fold recognition techniques in combination with a scaffold-based automatic mapping of disulfide bonds to define a 3D profile of the chemokine protein family. By applying our methodology to all currently uncharacterized human protein sequences, we have discovered two novel proteins that, without having significant sequence similarity to known chemokines or characteristic cysteine patterns, show strong structural resemblance to known anti-HIV chemokines. Detailed computational analysis and experimental structural investigations based on mass spectrometry and circular dichroism support our structural predictions and highlight several other chemokine-like features. The results obtained support their functional annotation as putative novel chemokines and encourage further experimental characterization. The identification of remote homologs of human chemokines may provide new insights into the molecular mechanisms causing pathologies such as cancer or AIDS, and may contribute to the development of novel treatments. Besides, the genome-wide applicability of our methodology based on 3D protein family profiles may open up new possibilities for improving and accelerating protein function annotation processes.
authors.affiliation: Structural Bioinformatics, BIOTEC TU Dresden, Germany.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Tomczak
authors.forename: Jana
authors.initials: J
authors.lastname: Sontheimer
authors.forename: David
authors.initials: D
authors.lastname: Drechsel
authors.forename: Rainer
authors.initials: R
authors.lastname: Hausdorf
authors.forename: Marc
authors.initials: M
authors.lastname: Gentzel
authors.forename: Andrej
authors.initials: A
authors.lastname: Shevchenko
authors.forename: Stefanie
authors.initials: S
authors.lastname: Eichler
authors.forename: Karim
authors.initials: K
authors.lastname: Fahmy
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
mesh_terms: D000595:Amino Acid Sequence; D018925:Chemokines / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D015894:Genome, Human; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D020543:Proteome / Q000032:analysis; D016415:Sequence Alignment
chemical_list: D018925:Chemokines; D011506:Proteins; D020543:Proteome