Architecture of a protein entry gate

Mokranjac, Dejana; Neupert, Walter

doi:10.1038/nature16318

Cited by 16 publications

(22 citation statements)

References 17 publications

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“…This observation suggests that mutations in NEMtGs can affect functions, such as electron transport and oxidative phosphorylation, protein translocation and mitochondrial biogenesis. The translocase of the outer membrane (TOM) complex is a clear example of the relevant role of mitonuclear genes in the cell, since nearly all mitochondrial pre-proteins are imported via a TOM entry gate (24). From the cytosol to the TOM complex, pre-proteins are guided by molecular chaperones (heat shock protein 90 or heat shock cognate 70) (25); there, TOM20, TOM22 and TOM70 recognize the mitochondrial targeting signals of cytosolic preproteins (Fig.…”

Section: Mitochondriamentioning

confidence: 99%

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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High lactate production in cells during growth under oxygen-rich conditions (aerobic glycolysis) is a hallmark of tumor cells, indicating the role of mitochondrial function in tumorigenesis. In fact, enhanced mitochondrial biogenesis and impaired quality control are frequently observed in cancer cells. Mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS), is present in thousands of copies per cell, and has a very high mutation rate. Mutations in mtDNA and nuclear DNA (nDNA) genes encoding proteins that are important players in mitochondrial biogenesis and function are involved in oncogenic processes. A wide range of germline mtDNA polymorphisms, as well as tumor mtDNA somatic mutations have been identified in diverse cancer types. Approximately 72% of supposed tumor-specific somatic mtDNA mutations reported, have also been found as polymorphisms in the general population. The ATPase 6 and NADH dehydrogenase subunit genes of mtDNA are the most commonly mutated genes in breast cancer (BC). Furthermore, nuclear genes playing a role in mitochondrial biogenesis and function, such as peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1), fumarate hydratase (FH) and succinate dehydrogenase (SDH) are frequently mutated in cancer. In this review, we provide an overview of the mitochondrial germline variants and mutations in cancer, with particular focus on those found in BC.

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Section: Mitochondriamentioning

confidence: 99%

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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“…However, only a small set of these proteins are synthesized in the mitochondria; most of the mitochondria functioning proteins (∼99%) are encoded by nuclear genes, and imported into the correct mitochondrial compartment by specific preprotein translocase complexes 3,5,15,16 . These complexes include the translocase of outer membrane (the TOM complex) 17-20 , the carrier translocase of inner membrane complex (the TIM22 complex) 21-24 , the presequence translocase of the inner membrane (the TIM23 complex) 4,19,25 , the sorting and assembly machinery (the SAM complex) 26,27 , and the mitochondrial import complex (the MIM complex) 28,29 , etc. These translocation machineries are crucial for mitochondrial biogenesis, dynamics, and function 3,4,30,31 .…”

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confidence: 99%

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Wang

Guan

et al. 2019

Preprint

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21Mitochondria play vital functions in cellular metabolism, homeostasis, and apoptosis 1-3 . 22 Most of the mitochondrial proteins are synthesized as precursors in the cytosol and 23 imported into mitochondria for folding or maturation 4,5 . The translocase TIM22 24 complex is responsible for the import of multiple hydrophobic carrier proteins that are 25 then folded in the inner membrane of mitochondria 6-8 . In mammalian cells, the TIM22 26 complex consists of at least six components, Tim22, Tim29, AGK, and three Tim 27 chaperones (Tim9, Tim10a and Tim10b) 9-14 . Here, we report the cryo-EM structure of 28 the human translocase TIM22 complex at an overall resolution of 3.7 angstrom. The 29 core subunit, Tim22, contains four transmembrane helices, forming a partial pore that is 30 open to the lipid bilayer. Tim29 is a single transmembrane protein that provides an 31 N-terminal helix to stabilize Tim22 and a C-terminal intermembrane space (IMS) 32 domain to connect AGK and two TIM chaperone hexamers to maintain complex 33 integrity. One TIM hexamer comprises Tim9 and Tim10a in a 3:3 molar ratio, and the 34 other consists of two Tim9 units, three Tim10a units, and one Tim10b unit. The latter 35 hexamer faces the intramembrane region of Tim22, likely providing the dock to load the 36 precursors to the partial pore of Tim22. Our structure serves as a molecular basis for 37 the mechanistic understanding of TIM22 complex function. 38 39 40 3Mitochondria are essential eukaryotic cellular organelles with multiple vital functions, 41 such as energetics, metabolism, and cellular signaling 1,2 . These functions are performed by 42 more than 1,000 proteins 3,5 . However, only a small set of these proteins are synthesized in the 43 mitochondria; most of the mitochondria functioning proteins (~99%) are encoded by nuclear 44 genes, and imported into the correct mitochondrial compartment by specific preprotein 45 translocase complexes 3,5,15,16 . These complexes include the translocase of outer membrane 46 (the TOM complex) 17-20 , the carrier translocase of inner membrane complex (the TIM22 47 7 toward the intermembrane space and interact with the Tim9/10a/10b hexamer. Helix 1 and 129 loop 1, similar to a hook, sinuously wind around the groove between the inner helices and the 130 outer helices of Tim9 and Tim10a. Helix 1 was nestled in a greasy pocket formed by Tim9 131 and Tim10a (Fig. 2b), and likely functioned as a plug to obstruct the hydrophobic carrier 132 precursor from wedging within the hexamer chaperone from this side (Extended Data Fig. 6a). 133The recently identified disease-related mutation (Val33Leu) of Tim22 was located in the helix 134 1 51 . 135 136 Specific interactions comprise van der Waals contacts and one hydrogen bond. 137

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“…Cleavable pre‐sequence containing precursor proteins are imported into the mitochondria via TOM and translocase of inner mitochondrial membrane (TIM), respectively [Kiebler et al. 1990; Chacinska et al., 2005; Mokranjac and Neupert, 2015; Moulin et al., 2019]. The pre‐sequence translocase‐associated motor (PAM) facilitates protein translocation into the matrix, where the mitochondrial processing peptidase (MPP) cleaves off the pre‐sequences [Hawlitschek et al., 1988; Kang et al., 1990; Horst et al., 1997; Mossmann et al., 2012; Moulin et al., 2019].…”

Section: Protein Import Pathways Into Mitochondriamentioning

confidence: 99%

“…Main channel‐forming protein of the complex is Tom40, which forms a 19 stranded β‐barrel structure and allows passage of unfolded proteins [Hill et al., 1998; Suzuki et al., 2004; Becker et al., 2005; Wang et al., 2020]. Tom40 is associated with three receptor proteins Tom20, Tom22 and Tom70 and three other small TOM proteins – Tom5, Tom6 and Tom7 [Hill et al., 1998; Mokranjac and Neupert, 2015; Shiota et al., 2015]. Tom70 and Tom20 are the receptor proteins responsible for recognition of the incoming precursors – Tom70 receptors serve as the docking sites for hydrophobic precursors, whereas Tom20 predominantly recognises substrates of the pre‐sequence pathway [Abe et al., 2000; Young et al., 2003; Otera et al., 2007; Becker et al., 2011; Papić et al., 2011; Backes et al., 2018; Opaliński et al., 2018].…”

Section: Protein Import Pathways Into Mitochondriamentioning

confidence: 99%

Mitochondrial protein import as a quality control sensor

Maity

Chakrabarti

2021

Biology of the Cell

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Mitochondria are organelles involved in various functions related to cellular metabolism and homoeostasis. Though mitochondria contain own genome, their nuclear counterparts encode most of the different mitochondrial proteins. These are synthesised as precursors in the cytosol and have to be delivered into the mitochondria. These organelles hence have elaborate machineries for the import of precursor proteins from cytosol. The protein import machineries present in both mitochondrial membrane and aqueous compartments show great variability in pre‐protein recognition, translocation and sorting across or into it. Mitochondrial protein import machineries also interact transiently with other protein complexes of the respiratory chain or those involved in the maintenance of membrane architecture. Hence mitochondrial protein translocation is an indispensable part of the regulatory network that maintains protein biogenesis, bioenergetics, membrane dynamics and quality control of the organelle. Various stress conditions and diseases that are associated with mitochondrial import defects lead to changes in cellular transcriptomic and proteomic profiles. Dysfunction in mitochondrial protein import also causes over‐accumulation of precursor proteins and their aggregation in the cytosol. Multiple pathways may be activated for buffering these harmful consequences. Here, we present a comprehensive picture of import machinery and its role in cellular quality control in response to defective mitochondrial import. We also discuss the pathological consequences of dysfunctional mitochondrial protein import in neurodegeneration and cancer.

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Architecture of a protein entry gate

Cited by 16 publications

References 17 publications

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

Cryo-EM Structure of the Human Mitochondrial Translocase TIM22 Complex

Mitochondrial protein import as a quality control sensor

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