Central role of Tim17 in mitochondrial presequence protein translocation

Laura F. Fielden, Jakob D. Busch, Sandra G. Merkt, Iniyan Ganesan, Conny Steiert, Hanna B. Hasselblatt, Jon V. Busto, Christophe Wirth, Nicole Zufall, Sibylle Jungbluth, Katja Noll, Julia M. Dung, Ludmila Butenko, Karina Malsburg, Hans-Georg Koch, Carola Hunte, Martin Laan () and Nils Wiedemann ()
Additional contact information
Laura F. Fielden: University of Freiburg
Jakob D. Busch: University of Freiburg
Sandra G. Merkt: University of Freiburg
Iniyan Ganesan: University of Freiburg
Conny Steiert: University of Freiburg
Hanna B. Hasselblatt: University of Freiburg
Jon V. Busto: University of Freiburg
Christophe Wirth: University of Freiburg
Nicole Zufall: University of Freiburg
Sibylle Jungbluth: Saarland University
Katja Noll: Saarland University
Julia M. Dung: University of Freiburg
Ludmila Butenko: University of Freiburg
Karina Malsburg: Saarland University
Hans-Georg Koch: University of Freiburg
Carola Hunte: University of Freiburg
Martin Laan: Saarland University
Nils Wiedemann: University of Freiburg

Nature, 2023, vol. 621, issue 7979, 627-634

Abstract: Abstract The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesized with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views, including regulatory and coupling functions, have been reported on the essential TIM23 subunit Tim17 (refs. 5–7). Here we mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.

Date: 2023
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DOI: 10.1038/s41586-023-06477-8

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