An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import.

Publication Type:

Journal Article

Authors:

Bachochin, Maxwell J; McGuire, Kelly L; Cook, Brian D; Ye, Qiaozhen; Silletti, Steven; Corbett, Kevin D; Komives, Elizabeth A; Herzik, Mark A

Source:

Structure, Volume 34, Issue 2, p.273-283.e6 (2026)

Keywords:

Allosteric Regulation, Binding Sites, Crystallography, X-Ray, Humans, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitochondrial Precursor Protein Import Complex Proteins, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, Protein Domains, Protein Transport

Abstract:

<p>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.</p>

PDB: 
9PKQ
Beamline: 
24-ID-C