Structures, functions and adaptations of the human LINE-1 ORF2 protein
Eric T. Baldwin,
Trevor van Eeuwen,
David Hoyos,
Arthur Zalevsky,
Egor P. Tchesnokov,
Roberto Sánchez,
Bryant D. Miller,
Luciano H. Di Stefano,
Francesc Xavier Ruiz,
Matthew Hancock,
Esin Işik,
Carlos Mendez-Dorantes,
Thomas Walpole,
Charles Nichols,
Paul Wan,
Kirsi Riento,
Rowan Halls-Kass,
Martin Augustin,
Alfred Lammens,
Anja Jestel,
Paula Upla,
Kera Xibinaku,
Samantha Congreve,
Maximiliaan Hennink,
Kacper B. Rogala,
Anna M. Schneider,
Jennifer E. Fairman,
Shawn M. Christensen,
Brian Desrosiers,
Gregory S. Bisacchi,
Oliver L. Saunders,
Nafeeza Hafeez,
Wenyan Miao,
Rosana Kapeller,
Dennis M. Zaller,
Andrej Sali,
Oliver Weichenrieder,
Kathleen H. Burns (),
Matthias Götte (),
Michael P. Rout (),
Eddy Arnold (),
Benjamin D. Greenbaum (),
Donna L. Romero (),
John LaCava () and
Martin S. Taylor ()
Additional contact information
Eric T. Baldwin: ROME Therapeutics
Trevor van Eeuwen: The Rockefeller University
David Hoyos: Memorial Sloan Kettering Cancer Center
Arthur Zalevsky: Department of Bioengineering and Therapeutic Sciences University of California, San Francisco
Egor P. Tchesnokov: University of Alberta
Roberto Sánchez: ROME Therapeutics
Bryant D. Miller: Dana Farber Cancer Institute and Harvard Medical School
Luciano H. Di Stefano: University Medical Center Groningen
Francesc Xavier Ruiz: Rutgers University
Matthew Hancock: Department of Bioengineering and Therapeutic Sciences University of California, San Francisco
Esin Işik: Dana Farber Cancer Institute and Harvard Medical School
Carlos Mendez-Dorantes: Dana Farber Cancer Institute and Harvard Medical School
Thomas Walpole: Chesterford Research Park
Charles Nichols: Chesterford Research Park
Paul Wan: Chesterford Research Park
Kirsi Riento: Chesterford Research Park
Rowan Halls-Kass: Chesterford Research Park
Martin Augustin: Proteros Biostructures GmbH, Martinsried
Alfred Lammens: Proteros Biostructures GmbH, Martinsried
Anja Jestel: Proteros Biostructures GmbH, Martinsried
Paula Upla: The Rockefeller University
Kera Xibinaku: Whitehead Institute for Biomedical Research
Samantha Congreve: Whitehead Institute for Biomedical Research
Maximiliaan Hennink: Whitehead Institute for Biomedical Research
Kacper B. Rogala: Stanford University School of Medicine
Anna M. Schneider: Max Planck Institute for Biology
Jennifer E. Fairman: Johns Hopkins University School of Medicine
Shawn M. Christensen: University of Texas at Arlington
Brian Desrosiers: ROME Therapeutics
Gregory S. Bisacchi: ROME Therapeutics
Oliver L. Saunders: ROME Therapeutics
Nafeeza Hafeez: ROME Therapeutics
Wenyan Miao: ROME Therapeutics
Rosana Kapeller: ROME Therapeutics
Dennis M. Zaller: ROME Therapeutics
Andrej Sali: Department of Bioengineering and Therapeutic Sciences University of California, San Francisco
Oliver Weichenrieder: Max Planck Institute for Biology
Kathleen H. Burns: Dana Farber Cancer Institute and Harvard Medical School
Matthias Götte: University of Alberta
Michael P. Rout: The Rockefeller University
Eddy Arnold: Rutgers University
Benjamin D. Greenbaum: Memorial Sloan Kettering Cancer Center
Donna L. Romero: ROME Therapeutics
John LaCava: The Rockefeller University
Martin S. Taylor: Massachusetts General Hospital and Harvard Medical School
Nature, 2024, vol. 626, issue 7997, 194-206
Abstract:
Abstract The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a ‘copy and paste’ mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p)1. ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer2,3, autoimmunity4,5 and ageing6,7, making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p ‘core’ (residues 238–1061, including the RT domain) by X-ray crystallography and cryo-electron microscopy in several conformational states. Our analyses identified two previously undescribed folded domains, extensive contacts to RNA templates and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed-ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry show that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signalling through cGAS/STING and resulting in interferon production6–8. In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which probably explains cytosolic priming. Other biochemical activities including processivity, DNA-directed polymerization, non-templated base addition and template switching together allow us to propose a revised L1 insertion model. Finally, our evolutionary analysis demonstrates structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on the evolutionary history of L1 and enable rational drug development targeting L1.
Date: 2024
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DOI: 10.1038/s41586-023-06947-z
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