Abstract:
:Understanding the role of specific amino acid residues in the molecular mechanism of a protein's function is one of the most challenging problems in modern biology. A systematic bioinformatic analysis of protein families and superfamilies can help in the study of structure-function relationships and in the design of improved variants of enzymes/proteins, but represents a methodological challenge. The pyridoxal-5'-phosphate (PLP)-dependent enzymes are catalytically diverse and include the aspartate aminotransferase superfamily which implements a common structural framework known as type fold I. In this work, the recently developed bioinformatic online methods Mustguseal and Zebra were used to collect and study a large representative set of the aspartate aminotransferase superfamily with high structural, but low sequence similarity to l-threonine aldolase from Aeromonas jandaei (LTAaj), in order to identify conserved positions that provide general properties in the superfamily, and to reveal family-specific positions (FSPs) responsible for functional diversity. The roles of the identified residues in the catalytic mechanism and reaction specificity of LTAaj were then studied by experimental site-directed mutagenesis and molecular modelling. It was shown that FSPs determine reaction specificity by coordinating the PLP cofactor in the enzyme's active centre, thus influencing its activation and the tautomeric equilibrium of the intermediates, which can be used as hotspots to modulate the protein's functional properties. Mutagenesis at the selected FSPs in LTAaj led to a reduction in a native catalytic activity and increased the rate of promiscuous reactions. The results provide insight into the structural basis of catalytic promiscuity of the PLP-dependent enzymes and demonstrate the potential of bioinformatic analysis in studying structure-function relationship in protein superfamilies.
journal_name
FEBS Open Biojournal_title
FEBS open bioauthors
Fesko K,Suplatov D,Švedas Vdoi
10.1002/2211-5463.12441subject
Has Abstractpub_date
2018-05-21 00:00:00pages
1013-1028issue
6issn
2211-5463pii
FEB412441journal_volume
8pub_type
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