Protein Active Site Motifs and Structure/Function Relationships
Zhenglin Hou, Chunlin Xiao, Hongzhan Huang, and Cathy H. WuABSTRACT
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.