On the emergence of p-loop ntpase and rossmann enzymes from a beta-alpha-beta ancestral fragment

Liam M. Longo, Jagoda Jabtoiiska, Pratik Vyas, Manil Kanade, Rachel Kolodny, Nir Ben-Tal, Dan S. Tawfik

Research output: Contribution to journalArticlepeer-review


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 PaP motif of both lineages, including the phosphate binding loop and a conserved aspartate at the tip of P2. 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 P2-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 PaP segment that comprises the core of these enzyme families to this very day.

Original languageEnglish
Article numbere64415
Pages (from-to)1-16
Number of pages16
StatePublished - Dec 2020

Bibliographical note

Funding Information:
This research has been supported by Grant 94747 by the Volkswagen Foundation. NB-T’s research is supported in part by the Abraham E Kazan Chair in Structural Biology, Tel Aviv University. DST is the Nella and Leon Benoziyo Professor of Biochemistry. We are grateful to Ita Gruic-Sovulj for her role in the analysis of the HUP domain that led to Figure 3, and to Andrei Lupas for insightful and critical comments.

Publisher Copyright:
© Longo et al.


  • AAA Proteins/chemistry
  • Binding Sites
  • Evolution, Molecular
  • Protein Structure, Tertiary
  • Sequence Alignment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)
  • Neuroscience (all)


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