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Cited by 7Protein Structure and DynamicsMitochondrial Function and PathologyHeat shock proteins research

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An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import

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Bachochin, Maxwell J., McGuire, Kelly L., Cook, Brian D., Ye, Qiaozhen, Silletti, Steven, Corbett, Kevin D., Komives, Elizabeth A., Herzik, Mark A.·2026·Structure
DOI 10.1016/j.str.2025.11.011PMC PMC13075491

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Abstract

Tom70 mediates mitochondrial protein import by coordinating transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 (HsTom70c) is entirely α-helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding and a C-terminal preprotein-binding domain. However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded HsTom70c, revealing two distinct conformations-open and closed-within the asymmetric unit. These states are stabilized by interdomain crystal contacts and supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and network analyses reveal a continuum of motion linking the NTD and CTD via key residues in helices α7, α8, and α25. Engagement of the CTD by viral protein Orf9b disrupts this network, stabilizing a partially closed intermediate and dampening distal NTD dynamics.

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Metadata

Authors
Bachochin, M. J., McGuire, K. L., Cook, B. D., Ye, Q., Silletti, S., Corbett, K. D., Komives, E. A., & Herzik, M. A.
Affiliations
University of California San Diego (US)
Corresponding author
Herzik, Mark A.
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
2026-02
Volume
34
Issue
2
Pages
273-283.e6
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/j.str.2025.11.011
PMC
PMC13075491
OpenAlex
W4417245545
Cited by
7
References
3
Citations by year
2026: 7
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Argonne National Laboratory (DE-AC02-06CH11357)
  • Research Corporation for Science Advancement
  • Office of Science
  • National Institutes of Health (R01-GM129325)
  • National Institute of General Medical Sciences (S10 OD016234, S10 OD021724, R35-GM138206, T32-GM008326, P30 GM124165)
  • Searle Scholars Program
  • U.S. Department of Energy
  • National Institute of Allergy and Infectious Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
Tom70, mitochondrial protein import, TOM complex, allosteric networks, conformational dynamics, TPR motif, ORF9b, SARS-CoV-2, interdomain contacts, crystal structure, hydrogen-deuterium exchange, molecular dynamics

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