Redefining the Limits of Functional Continuity in the Early Evolution of P-Loop NTPases
(2025) In Molecular biology and evolution 42(4).- Abstract
At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this six to eight residue motif could have sparked the emergence of the very first nucleoside triphosphatases—a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected. Simulations suggest that phosphate binding is nonspecific, with a preference for GTP over... (More)
At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this six to eight residue motif could have sparked the emergence of the very first nucleoside triphosphatases—a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected. Simulations suggest that phosphate binding is nonspecific, with a preference for GTP over orthophosphate. Control peptides with the same amino acid composition but different sequences and situated conformations behaved similarly to the Walker A peptides, revealing no indication that the Walker A sequence is privileged as a disembodied peptide. We conclude that the evolutionary history of the P-loop NTPase family is unlikely to have started with a disembodied Walker A peptide in an aqueous environment. The limits of evolutionary continuity for this protein family must be reconsidered. Finally, we argue that motifs such as the Walker A motif may represent incomplete or fragmentary molecular fossils—the true nature of which has been eroded by time.
(Less)
- author
- Demkiv, Andrey O.
; Toledo-Patiño, Saacnicteh
; Medina-Carmona, Encarnación
; Berg, Andrej
; Pinto, Gaspar P.
; Parracino, Antonietta
; Sanchez-Ruiz, Jose M.
; Hengge, Alvan C.
; Laurino, Paola
; Longo, Liam M.
and Kamerlin, Shina Caroline Lynn
LU
(Less) - organization
- publishing date
- 2025-04-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- molecular fossil, P-loop NTPase, phosphate-binding loop, primitive proteins, Walker A motif
- in
- Molecular biology and evolution
- volume
- 42
- issue
- 4
- article number
- msaf055
- publisher
- Oxford University Press
- external identifiers
-
- pmid:40070202
- scopus:105001941484
- ISSN
- 0737-4038
- DOI
- 10.1093/molbev/msaf055
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © The Author(s) 2025. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.
- id
- b5fb5a84-a837-459e-b24d-46159ed8c922
- date added to LUP
- 2025-08-22 15:03:37
- date last changed
- 2025-09-05 16:15:50
@article{b5fb5a84-a837-459e-b24d-46159ed8c922,
abstract = {{<p>At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this six to eight residue motif could have sparked the emergence of the very first nucleoside triphosphatases—a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected. Simulations suggest that phosphate binding is nonspecific, with a preference for GTP over orthophosphate. Control peptides with the same amino acid composition but different sequences and situated conformations behaved similarly to the Walker A peptides, revealing no indication that the Walker A sequence is privileged as a disembodied peptide. We conclude that the evolutionary history of the P-loop NTPase family is unlikely to have started with a disembodied Walker A peptide in an aqueous environment. The limits of evolutionary continuity for this protein family must be reconsidered. Finally, we argue that motifs such as the Walker A motif may represent incomplete or fragmentary molecular fossils—the true nature of which has been eroded by time.</p>}},
author = {{Demkiv, Andrey O. and Toledo-Patiño, Saacnicteh and Medina-Carmona, Encarnación and Berg, Andrej and Pinto, Gaspar P. and Parracino, Antonietta and Sanchez-Ruiz, Jose M. and Hengge, Alvan C. and Laurino, Paola and Longo, Liam M. and Kamerlin, Shina Caroline Lynn}},
issn = {{0737-4038}},
keywords = {{molecular fossil; P-loop NTPase; phosphate-binding loop; primitive proteins; Walker A motif}},
language = {{eng}},
month = {{04}},
number = {{4}},
publisher = {{Oxford University Press}},
series = {{Molecular biology and evolution}},
title = {{Redefining the Limits of Functional Continuity in the Early Evolution of P-Loop NTPases}},
url = {{http://dx.doi.org/10.1093/molbev/msaf055}},
doi = {{10.1093/molbev/msaf055}},
volume = {{42}},
year = {{2025}},
}