PT  - JOURNAL ARTICLE
AU  - Liam M. Longo
AU  - Jagoda Jabłońska
AU  - Pratik Vyas
AU  - Manil Kanade
AU  - Rachel Kolodny
AU  - Nir Ben-Tal
AU  - Dan S. Tawfik
TI  - On the Emergence of P-Loop NTPase and Rossmann Enzymes from a Beta-Alpha-Beta Ancestral Fragment
AID  - 10.1101/2020.07.15.204123
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.15.204123
4099  - http://biorxiv.org/content/early/2020/10/20/2020.07.15.204123.short
4100  - http://biorxiv.org/content/early/2020/10/20/2020.07.15.204123.full
AB  - Dating back to the last universal common ancestor (LUCA), the P-loop NTPases and Rossmanns now comprise the most ubiquitous and diverse enzyme lineages. Intriguing similarities in their overall architecture and phosphate binding motifs suggest common ancestry; however, due to a lack of sequence identity and some fundamental structural differences, these families are considered independent emergences. To address this longstanding dichotomy, we systematically searched for ‘bridge proteins’ with structure and sequence elements shared by both lineages. We detected homologous segments that span the first βαβ segment of both lineages and include two key functional motifs: (i) a phosphate binding loop – the ‘Walker A’ motif of P-loop NTPases or the Rossmann equivalent, both residing at the N-terminus of α1; and (ii) an Asp at the tip of β2. The latter comprises the ‘Walker B’ aspartate that chelates the catalytic metal in P-loop NTPases, or the canonical Rossmann β2-Asp that binds the cofactor’s ribose moiety. Tubulin, a Rossmann GTPase, demonstrates the potential of the β2-Asp to take either one of these two roles. We conclude that common P-loops/Rossmann ancestry is plausible, although convergence cannot be completely ruled out. Regardless, both lineages most likely emerged from a polypeptide comprising a βαβ segment carrying the above two functional motifs, a segment that comprises the core of both enzyme families to this very day.Competing Interest StatementThe authors have declared no competing interest.