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Structure-based functional motif identifies a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 subfamily

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA

¹Correspondence: GeneFormatics, Inc., 5830 Oberlin Dr., Ste. 200, San Diego, CA 92121, USA. E-mail: jacque{at}geneformatics.com

In previous work, 3-dimensional descriptors of protein function (`fuzzy functional forms') were used to identify disulfide oxidoreductase active sites in high-resolution protein structures. During this analysis, a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 (PP1) crystal structure was discovered. In PP1, the potential redox active site is located in close proximity to the phosphatase active site. This result is interesting in view of literature suggesting that serine/threonine phosphatases could be subject to redox control mechanisms within the cell; however, the actual source of this control is unknown. Additional analysis presented here shows that the putative oxidoreductase active site is highly conserved in the serine/threonine phosphatase-1 subfamily, but not in the serine/threonine phosphatase-2A or -2B subfamilies. These results demonstrate the significant advantages of using structure-based motifs for protein functional site identification. First, a putative disulfide oxidoreductase active site has been identified in serine-threonine phosphatases using a descriptor built from the glutaredoxin/thioredoxin family, proteins that have no apparent evolutionary relationship whatsoever to the PP1 proteins. Second, the proximity of the putative disulfide oxidoreductase active site to the phosphatase active site provides evidence toward a regulatory control mechanism. No sequence-based method could provide either piece of information.—Fetrow, J. S., Siew, N., Skolnick, J. Structure-based functional motif identifies a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 subfamily.

Key Words: functional genomics • function prediction • structural genomics • structure-based function annotation • fuzzy functional form

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