Tim23 is an essential channel-forming subunit of the presequence translocase recruiting multiple components for assembly of the core complex, thereby regulating the protein translocation process. However, understanding of the precise interaction of subunits associating with Tim23 remains largely elusive. Our findings highlight that transmembrane helix 1 (TM1) is required for homodimerization of Tim23, while, together with TM2, it is involved in preprotein binding within the channel. Based on our evidence, we predict that the TM1 and TM2 from each dimer are involved in the formation of the central translocation pore, aided by Tim17. Furthermore, TM2 is also involved in the recruitment of Tim21 and the presequence-associated motor (PAM) subcomplex to the Tim23 channel, while the matrix-exposed loop L1 generates specificity in their association with the core complex. Strikingly, our findings indicate that the C-terminal sequence of Tim23 is dispensable for growth and functions as an inhibitor for binding of Tim21. Our model conceptually explains the cooperative function between Tam41 and Pam17 subunits, while the antagonistic activity of Tim21 predominantly determines the bound and free forms of the PAM subcomplex during import. Mitochondria are indispensable organelles required for a wide spectrum of cellular processes, including energy metabolism. The mitochondrial genome encodes only a few proteins across the kingdoms, ranging from 7 in Saccharomyces cerevisiae to 13 in humans (1, 2). Almost all the several hundreds of proteins residing in various mitochondrial compartments are encoded by the nuclear genome and synthesized on cytosolic ribosomes. Therefore, active mitochondrial function and biogenesis require efficient protein transport destined for the different subcompartments (1-9). Greater than 60% of mitochondrial proteins are targeted to the matrix compartment and are translocated through the presequence translocase (Tim23 complex), an inner membranebound multisubunit machinery whose components are highly conserved. The presequence translocase consists of central channel-forming components mainly constituted by the Tim23 protein together with Tim17, which maintains the integrity of the translocation pore (10-15), while other subunits, such as Tim50 and Tim21, which contains a single transmembrane helix with a large intermembrane space (IMS)-exposed domain, assist with presorting and guided channeling of preproteins via interaction with the translocase of outer membrane (TOM) complex (16)(17)(18)(19)(20). Besides channel-forming components, the Tim23 complex recruits a peripherally associated import motor whose functions are essential for the translocation of proteins destined for the matrix compartment (21-23). Mitochondrial heat shock protein Hsp70 (Ssc1 in yeast) forms the core of the import motor recruited for preprotein binding in the ATP-bound state to the channel via a membrane tether, Tim44 (21-24). Tim44 provides the platform and recruits two additional terminal regulatory components, J protein Pam...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.