Abstract
The group of proteins that contain a thioredoxin (Trx) fold is huge and diverse. Assessment of the variation in catalytic machinery of Trx fold proteins is essential in providing a foundation for understanding their functional diversity and predicting the function of the many uncharacterized members of the class. The proteins of the Trx fold class retain common features—including variations on a dithiol CxxC active site motif—that lead to delivery of function. We use protein similarity networks to guide an analysis of how structural and sequence motifs track with catalytic function and taxonomic categories for 4,082 representative sequences spanning the known superfamilies of the Trx fold. Domain structure in the fold class is varied and modular, with 2.8% of sequences containing more than one Trx fold domain. Most member proteins are bacterial. The fold class exhibits many modifications to the CxxC active site motif—only 56.8% of proteins have both cysteines, and no functional groupings have absolute conservation of the expected catalytic motif. Only a small fraction of Trx fold sequences have been functionally characterized. This work provides a global view of the complex distribution of domains and catalytic machinery throughout the fold class, showing that each superfamily contains remnants of the CxxC active site. The unifying context provided by this work can guide the comparison of members of different Trx fold superfamilies to gain insight about their structure-function relationships, illustrated here with the thioredoxins and peroxiredoxins.
Highlights
It has been established that protein structures incorporate new variations on an ancestral fold in evolving diverse functions [1]
The class comprises a broad collection of protein superfamilies that are unified by their shared use of the small thioredoxin (Trx) domain—consisting of a four-stranded beta sheet sandwiched by three alpha helices—and diversified by the many molecular functions catalyzed by members of the fold class
While some of the sequence groups associated with uniquely eukaryotic biological roles have already been discussed here, the comparative genomics panorama provided by the network implicates other classes of Trx fold proteins in ancient and critical functions such that the fold has been conserved in sequence and structure from prokaryote to animal; these include the classic thioredoxins involved in reduction of ribonucleotide reductase; glutathione peroxidases; the cytosolic GSTs including the omega, zeta, and theta ‘‘subgroups’’; and the peroxiredoxins (Fig. 6G,K,J, Fig. 7P–Q)
Summary
It has been established that protein structures incorporate new variations on an ancestral fold in evolving diverse functions [1]. Domains recombine in modular units, are decorated with insertions and extensions of loops and secondary structure elements [2], and sometimes they drift [3]. How these large revisions to a fold can extend and transform the catalytic capabilities of a protein is less understood for a number of reasons, namely that the catalytic changes are system-specific and that trends can often only be detected through observing the full landscape of variations of the fold. The thioredoxin fold class is a prime example of why such a clarification is desirable; members evince extreme levels of structural and functional variation when compared with the canonical thioredoxin enzyme. The archetypal catalytic mechanism in the Trx fold class involves the reduction of a disulfide bond in a protein substrate using a dithiol CxxC active
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