Protein Active Site Motifs and Structure/Function Relationships

Zhenglin Hou, Chunlin Xiao, Hongzhan Huang, and Cathy H. Wu
Protein Information Resource, National Biomedical Research Foundation,
Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20007-2195


Fold classification is considered a powerful means for functional assignments of proteins; however, recent studies have indicated that the relationship between fold and function has only limited predictive value. To gain insights into the structure/function association, proteins can be divided into two components based on structures: structurally important portion (SIP), which determines the overall fold, and functionally important portion (FIP), which influences protein activity. Our objective is to develop a FIP database with active site motifs for studying structure/function relationships, complementary to SIP classification in SCOP and CATH. As a case study, we have analyzed the FIP in adenylosuccinate synthetase, which is only distantly related to G-proteins in overall sequence and fold but shares a remarkable similarity in GTP binding elements. 1D-3D alignments of the synthetase superfamily reveal several highly conserved motifs for GTP biding and IMP and L-aspartate recognition, most of which are not described in PROSITE or other databases. Cross-family comparison between synthetases and G-proteins shows that two motifs essential for G-protein signaling are modified in synthetases, resulting in functional variation. Such examples of convergent evolution in function but divergent evolution in fold are used in our prototype FIP database. [Supported in part by NIH grant #P41 LM05798].

Presented at the 4th Annual Conference on Computational Genomics, Baltimore, MD, 2000.

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