{
  "abstract": "Supramolecular assemblies are integral to cellular biochemical processes, relying on their dynamic nature to fulfill essential functions. The protease ClpP1P2, paired with ATPase partners ClpC1 or ClpX, is vital for the survival of Mycobacterium tuberculosis ( Mtb ). While the ClpP1P2 complex requires activation by specific N-blocked dipeptides (e.g., Z-Leu-Leu) to exhibit proteolytic activity in vitro, the mechanism of in vivo activation remains unclear. In this study, we identified novel activators that enabled the structural determination of the ClpC1P1P2 complex, providing insights into its assembly. Furthermore, we discovered that trehalose - a key metabolite and molecular crowding agent in Mtb , significantly enhances the activity of both ClpC1P1P2 and ClpXP1P2 complexes without the need for activating peptides. Analytical ultracentrifugation revealed that trehalose promotes the formation of these active complexes, mimicking intracellular conditions. These findings propose a new model of Clp system activation in vivo , offering promising avenues for therapeutic targeting in tuberculosis treatment. Significance Statement The proteolytic complex formed by the essential proteins ClpP1 and ClpP2, along with their specific ATP-dependent activators ClpX and ClpC1, has emerged as a highly attractive target for anti-tuberculosis drug development. While previous studies have shown that ClpP1P2 can be activated in vitro by small peptide activators, its in vivo activation mechanism remains unclear. In this study, we identify novel activators and demonstrate that trehalose, a key metabolite in Mycobacterium tuberculosis , enhances ClpC1P1P2 and ClpXP1P2 activity without the need for activating peptides. These findings propose a new model for Clp system activation in Mycobacterium tuberculosis , advancing our understanding of its regulation and potential as a therapeutic target.",
  "abstract_shown": true,
  "affiliations": [
    "i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal",
    "Universidade do Porto Instituto de Investigacao e Inovacao em Saude",
    "Harvard Chan School of Public Health, Department of Immunology and Infectious Diseases, Harvard University, Cambridge, MA, USA",
    "Harvard School of Public Health",
    "Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Lisbon, Portugal",
    "Instituto de Tecnologia Quimica e Biologica",
    "Cryo-EM Facility, Department of Macromolecular Structures, Centro Nacional de Biotecnología-CSIC, Madrid, Spain; Department of Macromolecular Structure, National Center of Biotechnology (CNB-CSIC), Madrid 28049, Spain",
    "Centro Nacional de Biotecnologia",
    "Cryo-EM Facility, Department of Macromolecular Structures, Centro Nacional de Biotecnología-CSIC, Madrid, Spain; Department of Macromolecular Structure, National Institute of Biotechnology (CNB-CSIC), Madrid 28049, Spain; Institute for Chemical Research (IIQ), Scientific Research Center Isla de la Cartuja (cicCartuja), University of Seville-CSIC, Seville, Spain",
    "Cryo-EM Facility, Department of Macromolecular Structures, Centro Nacional de Biotecnología-CSIC, Madrid, Spain; Department of Macromolecular Structure, National Institute of Biotechnology (CNB-CSIC), Madrid 28049, Spain",
    "Plateforme de biophysique moléculaire, C2RT, Institut Pasteur, Université Paris Cité, 75015 Paris, France",
    "Institut Pasteur",
    "Tufts University School of Medicine",
    "Department of Developmental, Molecular and Chemical Biology, Tufts, Medford, MA, USA",
    "Harvard Medical School",
    "Institut de Chimie des Substances Naturelles (ICSN), Centre national de la recherche scientifique (CNRS), Gif-Sur-Yvette, Paris, France",
    "Department of Cell Biology, Harvard Medical School, Boston, MA, USA",
    "Faculdade de Medicina da Universidade do Porto",
    "Harvard Chan School of Public Health, Department of Immunology and Infectious Diseases, Harvard University, Cambridge, MA, USA. Electronic address: erubin@hsph.harvard.edu",
    "i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Electronic address: hugo.fraga@i3s.up.pt"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Katharina Weinhäupl",
      "orcid": "0000-0002-9552-9876"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Tatos N. Akopian"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Dmitry A. Semchonok",
      "orcid": "0000-0003-1622-9443"
    },
    {
      "affs": [
        2,
        5
      ],
      "name": "Olga Krandor"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Rocío Arranz",
      "orcid": "0000-0001-5321-0915"
    },
    {
      "affs": [
        8
      ],
      "name": "M. Teresa Bueno-Carrasco",
      "orcid": "0000-0003-1586-2589"
    },
    {
      "affs": [
        9,
        7
      ],
      "name": "Marcos Gragera",
      "orcid": "0000-0002-3097-1743"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Maelenn Chevreuil",
      "orcid": "0000-0003-4885-5609"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Bertrand D. E. Raynal",
      "orcid": "0000-0001-5634-0408"
    },
    {
      "affs": [
        2,
        12
      ],
      "name": "Samuel Zinga"
    },
    {
      "affs": [
        13,
        12
      ],
      "name": "Yuxin Liu"
    },
    {
      "affs": [
        13,
        12
      ],
      "name": "Jack Hung-Sen Lai",
      "orcid": "0009-0003-4566-1961"
    },
    {
      "affs": [
        13,
        12
      ],
      "name": "Wengen Wu"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "William W. Bachovchin",
      "orcid": "0000-0002-9926-7244"
    },
    {
      "affs": [
        15,
        3
      ],
      "name": "Diego F. Gauto",
      "orcid": "0000-0003-3757-2830"
    },
    {
      "affs": [
        16,
        17
      ],
      "name": "Alfred Lewis Goldberg",
      "orcid": "0000-0002-8319-5856"
    },
    {
      "affs": [
        18
      ],
      "name": "Eric J. Rubin",
      "orcid": "0000-0001-5120-962X"
    },
    {
      "affs": [
        19
      ],
      "name": "Hugo Fraga",
      "orcid": "0000-0001-7677-4086"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/22s6thwcgxmws.bib",
  "cited_by": 7,
  "doi": "10.1016/j.celrep.2026.117400",
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  "issns": [
    "2211-1247",
    "2639-1856"
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  "landing_url": "https://doi.org/10.1016/j.celrep.2026.117400",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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  "openalex": "W4408079549",
  "pdf_url": null,
  "pmcid": null,
  "pmid": "42213777",
  "published": "2026-05-30",
  "publisher": "Cell Press",
  "ris": "https://research.draconitic.com/paper/22s6thwcgxmws.ris",
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      "first_seen": "2026-10-30T13:26:48Z",
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      "url": "https://doi.org/10.1016/j.celrep.2026.117400"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Heat shock proteins research",
      "subfield": "molecular-biology"
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  ],
  "title": "Activation mechanism and structural assembly of the Mycobacterium tuberculosis ClpP1P2 protease and its associated ATPases",
  "title_text": "Activation mechanism and structural assembly of the Mycobacterium tuberculosis ClpP1P2 protease and its associated ATPases",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T13:20:30Z",
  "url": "https://research.draconitic.com/paper/22s6thwcgxmws",
  "venue": "Cell Reports",
  "versions": []
}