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J Struct Funct Genomics. 2010 Mar;11(1):51-9. doi: 10.1007/s10969-010-9086-7. Epub 2010 Apr 11.

High-throughput computational structure-based characterization of protein families: START domains and implications for structural genomics.

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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.


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.

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