Abstract
This article is dedicated to the memory of Michael G. Rossmann. Dating back to the last universal common ancestor, P-loop NTPases and Rossmanns comprise the most ubiquitous and diverse enzyme lineages. Despite similarities in their overall architecture and phosphate binding motif, a lack of sequence identity and some fundamental structural differences currently designates them as independent emergences. We systematically searched for structure and sequence elements shared by both lineages. We detected homologous segments that span the first βαβ motif of both lineages, including the phosphate binding loop and a conserved aspartate at the tip of β2. The latter ligates the catalytic metal in P-loop NTPases, while in Rossmanns it binds the nucleotide's ribose moiety. Tubulin, a Rossmann GTPase, demonstrates the potential of the β2-Asp to take either one of these two roles. While convergence cannot be completely ruled out, we show that both lineages likely emerged from a common βαβ segment that comprises the core of these enzyme families to this very day.
Highlights
In 1970, Michael Rossmann reported the structure of the first aba sandwich protein, lactate dehydrogenase (Adams et al, 1970)
Essentially all studies aimed at unraveling the history of protein evolution concluded that these enzymes emerged well before the last universal common ancestor (LUCA), and were among the very first, if not the first, enzyme families (Leipe et al, 2003; Ma et al, 2008; Edwards et al, 2013; Alva et al, 2015; Aravind et al, 2002a; Goncearenco and Berezovsky, 2015)
Aba sandwich proteins consist of a tandem repeat of b-loop-a elements, where the loops form the active-site
Summary
In 1970, Michael Rossmann reported the structure of the first aba sandwich protein, lactate dehydrogenase (Adams et al, 1970). On the basis of a sequence analysis, another major aba sandwich domain that utilizes phosphorylated nucleosides was proposed (Walker et al, 1982), which is known as the P-loop NTPase, or ‘P-loop’ for short The importance of these two evolutionary lineages, Rossmanns and P-loops, cannot be overstated: Both lineages have diversified extensively, and each is individually associated with more than 120 families and 75 different enzymatic reactions (see Methods). Both P-loops and Rossmanns are dubbed nucleotide-binding domains because they both make use of phosphorylated ribonucleosides such as ATP or NAD, as well as of other pre-LUCA cofactors such as SAM (Laurino et al, 2016)
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