High-throughput computational structure-based characterization of protein families: START domains and implications for structural genomics.
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.
Lee
Hunjoong
H
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.
Li
Zhaohui
Z
Silkov
Antonina
A
Fischer
Markus
M
Petrey
Donald
D
Honig
Barry
B
Murray
Diana
D
D019295:Computational Biology; D016678:Genome; D023281:Genomics / Q000379:methods*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D011506:Proteins
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W299-302
15980475
Structure. 2009 Jun 10;17(6):869-81
19523904
Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
12824332
Nucleic Acids Res. 2008 Jan;36(Database issue):D281-8
18039703
Annu Rev Biophys. 2009;38:371-83
19416074
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13597-602
9811845
Nat Struct Biol. 2000 May;7(5):408-14
10802740
J Mol Biol. 1993 Dec 5;234(3):779-815
8254673
Genome Biol. 2004;5(6):R41
15186492
J Cell Sci. 2005 Jul 1;118(Pt 13):2791-801
15976441
Biochim Biophys Acta. 2007 Jun;1771(6):644-53
17314061
Nature. 2005 Sep 1;437(7055):154-8
16136145
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W327-31
15215404
Proteins. 1991;11(4):281-96
1758883
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D23-6
14681350
Biochim Biophys Acta. 2007 Jun;1771(6):654-62
17499021
Methods Enzymol. 1997;277:396-404
9379925
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17377-82
19805138
Am J Pharmacogenomics. 2004;4(4):247-52
15287818
Proteins. 2007 Mar 1;66(4):766-77
17154423
J Mol Graph. 1995 Oct;13(5):323-30, 307-8
8603061
Nat Struct Biol. 1996 Dec;3(12):1040-5
8946858
J Struct Funct Genomics. 2009 Mar;10(1):1-8
19037750
J Biol Chem. 2005 Dec 30;280(52):42627-35
16230336
Proteins. 1993 Dec;17(4):355-62
8108378
Structure. 2009 Feb 13;17(2):151-9
19217386
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
FEBS Lett. 2006 Oct 9;580(23):5436-41
16828756
BMC Evol Biol. 2008 Oct 15;8:286
18922149
Nucleic Acids Res. 2009 Jan;37(Database issue):D365-8
19010965
Mol Cell Endocrinol. 2003 Apr 28;202(1-2):59-65
12770731
Genome Res. 2002 Oct;12(10):1619-23
12368255
Acta Crystallogr D Biol Crystallogr. 1994 Mar 1;50(Pt 2):178-85
15299456
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64
9600884
Nat Struct Biol. 2002 Jul;9(7):507-11
12055623