Structural insight into the SAM-mediated assembly of the mitochondrial TOM core complex

Wang, Qiang; Guan, Zeyuan; Qi, Liqun; Zhuang, Jinjin; Wang, Chen; Hong, Sixing; Lv, Yan; Wu, Yan; Cao, Xiaoqian; Cao, Jianbo; Yan, Junjie; Zou, Tingting; Liu, Zhu; Zhang, Delin; Yan, Chuangye; Yin, Ping

doi:10.1126/science.abh0704

Cited by 31 publications

(34 citation statements)

References 46 publications

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“…This has the effect of limiting the amount of Mdm10 which is able to bind to the SAM complex thus inhibiting TOM complex assembly. Cryo-EM experiments have recently generated high resolution structures of the SAM complex from M. thermophila and S. cerevisiae in complex with various substrates providing more evidence to support the mechanisms of outer membrane protein insertion discussed above (Diederichs et al, 2020;Takeda et al, 2021;Wang et al, 2021). The structural data clearly show a lateral opening in Sam50 between the β-signal in strand 16 and strand 1.…”

Section: Outer Membrane Protein Biogenesismentioning

confidence: 90%

“…The outer membrane therefore represents a significant barrier for these proteins which they must cross in order to be correctly assembled into both the inner and outer mitochondrial membranes. The entry gate that controls this import process is known as the TOM complex and is composed of a β-barrel pore forming protein (Tom40), a number of accessory/ scaffolding proteins (Tom5, Tom6 and Tom7) and two receptor proteins (Tom20 and Tom70) that recognise mitochondrial targeting signals within protein sequences (Bolliger et al, 1995;Dietmeier et al, 1997;Rapaport and Neupert, 1999;Model et al, 2001;Gabriel et al, 2003;Mokranjac and Neupert, 2015;Pfanner et al, 2019;Wang et al, 2021). Additionally, the TOM complex contains a protein called Tom22, which appears to act as both a receptor and a scaffolding protein helping to control the number of pore-forming subunits associated to each fully assembled TOM complex as well as facilitating protein import (Lithgow et al, 1994;Bolliger et al, 1995;Moczko et al, 1997;Yano et al, 2000).…”

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

“…(Kiebler et al, 1990), however it is only with recent advances in techniques such as cryo-EM that the assembly pathway of the TOM complex has become clearer. The assembly of the TOM complex is separated into three distinct stages known as assembly I, assembly II and TOM core assembly (Wang et al, 2021) (Figure 2A). Assembly I involves the integration of the Tom40 β-barrel protein into the outer membrane from the intermembrane space (IMS) side of the outer membrane via the sorting and assembly machinery (SAM) complex (this process will be discussed in detail later) (Wiedemann et al, 2003).…”

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

“…Tom5 and Tom6 are subsequently inserted and assembled with Tom40 while it is still associated with the SAM complex (Dietmeier et al, 1997;Model et al, 2001;Becker et al, 2010;Thornton et al, 2010). The subsequent addition of Tom7 leads to dissociation of the growing TOM complex from SAM and constitutes assembly II (Yamano et al, 2010;Becker et al, 2011b;Wang et al, 2021). The addition of Tom22 to the complex leads to the assembly of the TOM core complex containing multiple fully assembled TOM complexes with Tom22 acting as a scaffold holding them together (Araiso et al, 2019;Tucker and Park, 2019;Wang et al, 2020b;Wang et al, 2021).…”

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

“…Sam35 is thought to be peripherally associated with the SAM complex facing the cytosol which is counterintuitive to a mechanistic understanding given that β-barrel proteins are inserted from the IMS side of the outer membrane. There is some evidence that Sam35 is actually embedded within the outer membrane through close interactions with Sam50 (Kutik et al, 2008), possibly within the pore of Sam50, although recent structural data do not support this hypothesis (Takeda et al, 2021;Wang et al, 2021).…”

Section: Outer Membrane Protein Biogenesismentioning

confidence: 99%

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Targeting and Insertion of Membrane Proteins in Mitochondria

Eaglesfield

Tokatlidis

2021

Front. Cell Dev. Biol.

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Mitochondrial membrane proteins play an essential role in all major mitochondrial functions. The respiratory complexes of the inner membrane are key for the generation of energy. The carrier proteins for the influx/efflux of essential metabolites to/from the matrix. Many other inner membrane proteins play critical roles in the import and processing of nuclear encoded proteins (∼99% of all mitochondrial proteins). The outer membrane provides another lipidic barrier to nuclear-encoded protein translocation and is home to many proteins involved in the import process, maintenance of ionic balance, as well as the assembly of outer membrane components. While many aspects of the import and assembly pathways of mitochondrial membrane proteins have been elucidated, many open questions remain, especially surrounding the assembly of the respiratory complexes where certain highly hydrophobic subunits are encoded by the mitochondrial DNA and synthesised and inserted into the membrane from the matrix side. This review will examine the various assembly pathways for inner and outer mitochondrial membrane proteins while discussing the most recent structural and biochemical data examining the biogenesis process.

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Section: Outer Membrane Protein Biogenesismentioning

confidence: 90%

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

Section: The Translocon Of the Outer Membrane Complex: The Main Gateway For Proteins To Cross The Outer Membranementioning

confidence: 99%

Section: Outer Membrane Protein Biogenesismentioning

confidence: 99%

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Targeting and Insertion of Membrane Proteins in Mitochondria

Eaglesfield

Tokatlidis

2021

Front. Cell Dev. Biol.

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Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia

Herrmann

Bykov

2023

FEBS Letters

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Mitochondrial protein importMitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory chain, mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol. Different import pathways direct proteins to their respective mitochondrial subcompartment (outer membrane, intermembrane space (IMS), inner membrane and matrix). Specific targeting signals in their sequence direct proteins to their target destination and allow the proteins to embark on their respective import pathway. The main import pathways are shown here on the poster and are introduced in the following, using the mitochondrial import system of the baker's yeast Saccharomyces cerevisiae as example. However, the mitochondrial import system of mammalian cells is highly similar and deviates only in minor aspects. Even the mitochondrial import machineries of less closely related eukaryotes, such as plants and trypanosomes, are very similar and adhere to the same general principles.

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Biogenesis of mitochondrial β‐barrel membrane proteins

Ganesan,

Busto,

Pfanner

et al. 2024

FEBS Open Bio

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β‐barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β‐barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β‐barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β‐barrel protein. The β‐strands of β‐barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50‐preprotein hybrid barrel. The assembled precursor β‐barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β‐barrel, termed the β‐barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer‐to‐inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER‐mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β‐barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.

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Structural insight into the SAM-mediated assembly of the mitochondrial TOM core complex

Cited by 31 publications

References 46 publications

Targeting and Insertion of Membrane Proteins in Mitochondria

Targeting and Insertion of Membrane Proteins in Mitochondria

Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia

Biogenesis of mitochondrial β‐barrel membrane proteins

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