scholarly journals Tim50’s presequence receptor domain is essential for signal driven transport across the TIM23 complex

2011 ◽  
Vol 195 (4) ◽  
pp. 643-656 ◽  
Author(s):  
Christian Schulz ◽  
Oleksandr Lytovchenko ◽  
Jonathan Melin ◽  
Agnieszka Chacinska ◽  
Bernard Guiard ◽  
...  
Keyword(s):  
Binding Sites ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Outer Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Targeting Signals ◽  
Receptor Domain

N-terminal targeting signals (presequences) direct proteins across the TOM complex in the outer mitochondrial membrane and the TIM23 complex in the inner mitochondrial membrane. Presequences provide directionality to the transport process and regulate the transport machineries during translocation. However, surprisingly little is known about how presequence receptors interact with the signals and what role these interactions play during preprotein transport. Here, we identify signal-binding sites of presequence receptors through photo-affinity labeling. Using engineered presequence probes, photo cross-linking sites on mitochondrial proteins were mapped mass spectrometrically, thereby defining a presequence-binding domain of Tim50, a core subunit of the TIM23 complex that is essential for mitochondrial protein import. Our results establish Tim50 as the primary presequence receptor at the inner membrane and show that targeting signals and Tim50 regulate the Tim23 channel in an antagonistic manner.

Plant mitochondrial protein import: mechanisms and control

1999 ◽  
Vol 26 (8) ◽  
pp. 725 ◽  
Author(s):  
James Whelan
Keyword(s):  
Protein Import ◽  
Current Knowledge ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Import ◽  
Future Directions ◽  
Receptor Structure ◽  
Processing Peptidase ◽  
Targeting Signals ◽  
And Control

The characterisation of components of the plant mitochondrial import apparatus along with the availability of over one hundred nuclear-encoded mitochondrial proteins allows the study of plant mitochondrial protein import in homologous systems. From these studies it has emerged that although similarities in the import process exist with other organisms, significance differences exist, such as receptor structure, location of processing peptidase and targeting signals. These differences mean that previous studies carried out in heterologous systems must be re-evaluated. Further studies into protein import in plants need to be directed at understanding the mechanism of import and how this process may be controlled. In this review the latter points will be dealt with in terms of summarising our current knowledge and possible future directions.

Msp1/ATAD1 in Protein Quality Control and Regulation of Synaptic Activities

2020 ◽  
Vol 36 (1) ◽  
pp. 141-164
Author(s):  
Lan Wang ◽  
Peter Walter
Keyword(s):  
Quality Control ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Quality ◽  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Neurotransmitter Receptors ◽  
Functional Specialization ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import

Mitochondrial function depends on the efficient import of proteins synthesized in the cytosol. When cells experience stress, the efficiency and faithfulness of the mitochondrial protein import machinery are compromised, leading to homeostatic imbalances and damage to the organelle. Yeast Msp1 (mitochondrial sorting of proteins 1) and mammalian ATAD1 (ATPase family AAA domain–containing 1) are orthologous AAA proteins that, fueled by ATP hydrolysis, recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. Msp1 also extracts proteins that have become stuck in the import channel. The extracted proteins are targeted for proteasome-dependent degradation or, in the case of mistargeted tail-anchored proteins, are given another chance to be routed correctly. In addition, ATAD1 is implicated in the regulation of synaptic plasticity, mediating the release of neurotransmitter receptors from postsynaptic scaffolds to allow their trafficking. Here we discuss how structural and functional specialization imparts the unique properties that allow Msp1/ATAD1 ATPases to fulfill these diverse functions and also highlight outstanding questions in the field.

scholarly journals Mitochondrial Protein Import

2004 ◽  
Vol 279 (44) ◽  
pp. 45701-45707 ◽  
Author(s):  
Masatoshi Esaki ◽  
Hidaka Shimizu ◽  
Tomoko Ono ◽  
Hayashi Yamamoto ◽  
Takashi Kanamori ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Tom Complex ◽  
Membrane Complex ◽  
Cytosolic Side

Protein translocation across the outer mitochondrial membrane is mediated by the translocator called the TOM (translocase of the outer mitochondrial membrane) complex. The TOM complex possesses two presequence binding sites on the cytosolic side (thecissite) and on the intermembrane space side (thetranssite). Here we analyzed the requirement of presequence elements and subunits of the TOM complex for presequence binding to thecisandtranssites of the TOM complex. The N-terminal 14 residues of the presequence of subunit 9 of F0-ATPase are required for binding to thetranssite. The interaction between the presequence and thecissite is not sufficient to anchor the precursor protein to the TOM complex. Tom7 constitutes or is close to thetranssite and has overlapping functions with the C-terminal intermembrane space domain of Tom22 in the mitochondrial protein import.

scholarly journals Towards a molecular mechanism underlying mitochondrial protein import through the TOM-TIM23 complex

2021 ◽  
Author(s):  
Holly C Ford ◽  
William John Allen ◽  
Goncalo C Pereira ◽  
Xia Liu ◽  
Mark S Dillingham ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Atp Hydrolysis ◽  
Driving Forces ◽  
Mitochondrial Protein ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Net Charge ◽  
Protein Insertion ◽  
Rate Limiting

Mitochondria contain over a thousand different proteins, which, aside from a few encoded on the mitochondrial genome, are translated in the cytosol and targeted for import. For the majority, the first port of call is the translocase of the outer membrane (TOM-complex); their onward journey is via a procession of alternative molecular machines, conducting transport to their final sub-compartment destination: the outer-mitochondrial membrane (OMM), inner-mitochondrial membrane (IMM), inter-membrane space (IMS) or matrix. The pre-sequence translocase of the inner-membrane (TIM23-complex) is responsible for importing proteins with cleavable pre-sequences, and comes in two distinct forms: the TIM23SORT complex mediates IMM protein insertion and the TIM23MOTOR complex is responsible for matrix import. Progress in understanding these transport mechanisms has, until recently, been hampered by the poor sensitivity and time-resolution of import assays. However, with the development of an assay based on split NanoLuc luciferase, we can now explore this process in greater detail. Here, we apply this new methodology to understand how ∆ψ and ATP hydrolysis, the two main driving forces for transport through the TIM23MOTOR complex, contribute to the import of pre-sequence-containing precursors (PCPs) with varying properties. Notably, we found that two major rate limiting steps define the PCP import time: passage of the PCP across the OMM and initiation of IMM transport by the pre-sequence. The rates of these steps are influenced by PCP properties such as size and net charge, but correlate poorly with the total amount of PCP imported - emphasising the importance of collecting rapid kinetic data to elucidating mechanistic detail. Our results also indicate that PCPs spend very little time in the TIM23 channel - presumably rapid success or failure of import is critical for maintaining mitochondrial health.

Dynamic organization of the mitochondrial protein import machinery

2016 ◽  
Vol 397 (11) ◽  
pp. 1097-1114 ◽  
Author(s):  
Sebastian P. Straub ◽  
Sebastian B. Stiller ◽  
Nils Wiedemann ◽  
Nikolaus Pfanner
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Membrane Dynamics ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Dynamic Cooperation

Abstract Mitochondria contain elaborate machineries for the import of precursor proteins from the cytosol. The translocase of the outer mitochondrial membrane (TOM) performs the initial import of precursor proteins and transfers the precursors to downstream translocases, including the presequence translocase and the carrier translocase of the inner membrane, the mitochondrial import and assembly machinery of the intermembrane space, and the sorting and assembly machinery of the outer membrane. Although the protein translocases can function as separate entities in vitro, recent studies revealed a close and dynamic cooperation of the protein import machineries to facilitate efficient transfer of precursor proteins in vivo. In addition, protein translocases were found to transiently interact with distinct machineries that function in the respiratory chain or in the maintenance of mitochondrial membrane architecture. Mitochondrial protein import is embedded in a regulatory network that ensures protein biogenesis, membrane dynamics, bioenergetic activity and quality control.

scholarly journals Mitochondrial protein import: An unexpected disulfide bond

2016 ◽  
Vol 214 (4) ◽  
pp. 363-365 ◽  
Author(s):  
Dejana Mokranjac
Keyword(s):  
Disulfide Bond ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Channel Gating ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Import ◽  
Cell Biol ◽  
Molecular Nature

Most mitochondrial proteins are imported through the TIM23 translocation channel, the structure and molecular nature of which are still unclear. In this issue, Ramesh et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201602074) show that the TIM23 subunit Tim17 contains a disulfide bond that is crucial for protein translocation and channel gating.

scholarly journals From cytosol to mitochondria: the beginning of a protein journey

2020 ◽  
Vol 401 (6-7) ◽  
pp. 645-661 ◽  
Author(s):  
Maria Clara Avendaño-Monsalve ◽  
José Carlos Ponce-Rojas ◽  
Soledad Funes
Keyword(s):  
Mitochondrial Biogenesis ◽  
Stress Responses ◽  
Protein Import ◽  
Protein Targeting ◽  
Mitochondrial Protein ◽  
Past Research ◽  
Membrane Receptors ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Import ◽  
The Past

AbstractMitochondrial protein import is one of the key processes during mitochondrial biogenesis that involves a series of events necessary for recognition and delivery of nucleus-encoded/cytosol-synthesized mitochondrial proteins into the organelle. The past research efforts have mainly unraveled how membrane translocases ensure the correct protein sorting within the different mitochondrial subcompartments. However, early steps of recognition and delivery remain relatively uncharacterized. In this review, we discuss our current understanding about the signals on mitochondrial proteins, as well as in the mRNAs encoding them, which with the help of cytosolic chaperones and membrane receptors support protein targeting to the organelle in order to avoid improper localization. In addition, we discuss recent findings that illustrate how mistargeting of mitochondrial proteins triggers stress responses, aiming to restore cellular homeostasis.

scholarly journals Assembly of the Mitochondrial Protein Import Channel

2010 ◽  
Vol 21 (18) ◽  
pp. 3106-3113 ◽  
Author(s):  
Thomas Becker ◽  
Bernard Guiard ◽  
Nicolas Thornton ◽  
Nicole Zufall ◽  
David A. Stroud ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Membrane Insertion ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Transmembrane Segments ◽  
Tom Complex ◽  
Assembly Pathway ◽  
Assembly Defect

The preprotein translocase of the outer mitochondrial membrane (TOM) consists of a central β-barrel channel, Tom40, and six proteins with α-helical transmembrane segments. The precursor of Tom40 is imported from the cytosol by a pre-existing TOM complex and inserted into the outer membrane by the sorting and assembly machinery (SAM). Tom40 then assembles with α-helical Tom proteins to the mature TOM complex. The outer membrane protein Mim1 promotes membrane insertion of several α-helical Tom proteins but also affects the biogenesis of Tom40 by an unknown mechanism. We have identified a novel intermediate in the assembly pathway of Tom40, revealing a two-stage interaction of the precursor with the SAM complex. The second SAM stage represents assembly of Tom5 with the precursor of Tom40. Mim1-deficient mitochondria accumulate Tom40 at the first SAM stage like Tom5-deficient mitochondria. Tom5 promotes formation of the second SAM stage and thus suppresses the Tom40 assembly defect of mim1Δ mitochondria. We conclude that the assembly of newly imported Tom40 is directly initiated at the SAM complex by its association with Tom5. The involvement of Mim1 in Tom40 biogenesis can be largely attributed to its role in import of Tom5.

scholarly journals A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1164
Author(s):  
Ashley S. Pitt ◽  
Susan K. Buchanan
Keyword(s):  
Human Health ◽  
Mitochondrial Membrane ◽  
Cancer Metabolism ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Outer Mitochondrial Membrane ◽  
Tom Complex ◽  
Complex Interactions ◽  
Health And Disease ◽  
Function Relationship

The central role mitochondria play in cellular homeostasis has made its study critical to our understanding of various aspects of human health and disease. Mitochondria rely on the translocase of the outer membrane (TOM) complex for the bulk of mitochondrial protein import. In addition to its role as the major entry point for mitochondrial proteins, the TOM complex serves as an entry pathway for viral proteins. TOM complex subunits also participate in a host of interactions that have been studied extensively for their function in neurodegenerative diseases, cardiovascular diseases, innate immunity, cancer, metabolism, mitophagy and autophagy. Recent advances in our structural understanding of the TOM complex and the protein import machinery of the outer mitochondrial membrane have made structure-based therapeutics targeting outer mitochondrial membrane proteins during mitochondrial dysfunction an exciting prospect. Here, we describe advances in understanding the TOM complex, the interactome of the TOM complex subunits, the implications for the development of therapeutics, and our understanding of the structure/function relationship between components of the TOM complex and mitochondrial homeostasis.

Mitochondrial diseases caused by dysfunctional mitochondrial protein import

2018 ◽  
Vol 46 (5) ◽  
pp. 1225-1238 ◽  
Author(s):  
Thomas Daniel Jackson ◽  
Catherine Sarah Palmer ◽  
Diana Stojanovski
Keyword(s):  
Mitochondrial Disease ◽  
Genetic Disease ◽  
Molecular Basis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Mitochondrial Proteins ◽  
Eukaryotic Cells ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Proteome

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

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