title: High-throughput computational structure-based characterization of protein families: START domains and implications for structural genomics.
abstract: SkyLine, a high-throughput homology modeling pipeline tool, detects and models true sequence homologs to a given protein structure. Structures and models are stored in SkyBase with links to computational function annotation, as calculated by MarkUs. The SkyLine/SkyBase/MarkUs technology represents a novel structure-based approach that is more objective and versatile than other protein classification resources. This structure-centric strategy provides a multi-dimensional organization and coverage of protein space at the levels of family, function, and genome. The concept of "modelability", the ability to model sequences on related structures, provides a reliable criterion for membership in a protein family ("leverage") and underlies the unique success of this approach. The overall procedure is illustrated by its application to START domains, which comprise a Biomedical Theme for the Northeast Structural Genomics Consortium as part of the Protein Structure Initiative. START domains are typically involved in the non-vesicular transport of lipids. While 19 experimentally determined structures are available, the family, whose evolutionary hierarchy is not well determined, is highly sequence diverse, and the ligand-binding potential of many family members is unknown. The SkyLine/SkyBase/MarkUs approach provides significant insights and predicts: (1) many more family members (approximately 4,000) than any other resource; (2) the function for a large number of unannotated proteins; (3) instances of START domains in genomes from which they were thought to be absent; and (4) the existence of two types of novel proteins, those containing dual START domain and those containing N-terminal START domains.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, Center for Computational Biology and Bioinformatics, 630 West 168th St. PH 7W 313, New York, NY 10032, USA.
authors.forename: Hunjoong
authors.initials: H
authors.lastname: Lee
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.forename: Antonina
authors.initials: A
authors.lastname: Silkov
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Donald
authors.initials: D
authors.lastname: Petrey
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.forename: Diana
authors.initials: D
authors.lastname: Murray
mesh_terms: D019295:Computational Biology; D016678:Genome; D023281:Genomics / Q000379:methods*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W299-302
references.pmid: 15980475
references.citation: Structure. 2009 Jun 10;17(6):869-81
references.pmid: 19523904
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references.pmid: 12824332
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D281-8
references.pmid: 18039703
references.citation: Annu Rev Biophys. 2009;38:371-83
references.pmid: 19416074
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13597-602
references.pmid: 9811845
references.citation: Nat Struct Biol. 2000 May;7(5):408-14
references.pmid: 10802740
references.citation: J Mol Biol. 1993 Dec 5;234(3):779-815
references.pmid: 8254673
references.citation: Genome Biol. 2004;5(6):R41
references.pmid: 15186492
references.citation: J Cell Sci. 2005 Jul 1;118(Pt 13):2791-801
references.pmid: 15976441
references.citation: Biochim Biophys Acta. 2007 Jun;1771(6):644-53
references.pmid: 17314061
references.citation: Nature. 2005 Sep 1;437(7055):154-8
references.pmid: 16136145
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W327-31
references.pmid: 15215404
references.citation: Proteins. 1991;11(4):281-96
references.pmid: 1758883
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D23-6
references.pmid: 14681350
references.citation: Biochim Biophys Acta. 2007 Jun;1771(6):654-62
references.pmid: 17499021
references.citation: Methods Enzymol. 1997;277:396-404
references.pmid: 9379925
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17377-82
references.pmid: 19805138
references.citation: Am J Pharmacogenomics. 2004;4(4):247-52
references.pmid: 15287818
references.citation: Proteins. 2007 Mar 1;66(4):766-77
references.pmid: 17154423
references.citation: J Mol Graph. 1995 Oct;13(5):323-30, 307-8
references.pmid: 8603061
references.citation: Nat Struct Biol. 1996 Dec;3(12):1040-5
references.pmid: 8946858
references.citation: J Struct Funct Genomics. 2009 Mar;10(1):1-8
references.pmid: 19037750
references.citation: J Biol Chem. 2005 Dec 30;280(52):42627-35
references.pmid: 16230336
references.citation: Proteins. 1993 Dec;17(4):355-62
references.pmid: 8108378
references.citation: Structure. 2009 Feb 13;17(2):151-9
references.pmid: 19217386
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: FEBS Lett. 2006 Oct 9;580(23):5436-41
references.pmid: 16828756
references.citation: BMC Evol Biol. 2008 Oct 15;8:286
references.pmid: 18922149
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D365-8
references.pmid: 19010965
references.citation: Mol Cell Endocrinol. 2003 Apr 28;202(1-2):59-65
references.pmid: 12770731
references.citation: Genome Res. 2002 Oct;12(10):1619-23
references.pmid: 12368255
references.citation: Acta Crystallogr D Biol Crystallogr. 1994 Mar 1;50(Pt 2):178-85
references.pmid: 15299456
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64
references.pmid: 9600884
references.citation: Nat Struct Biol. 2002 Jul;9(7):507-11
references.pmid: 12055623