Molecular Basis of the Dynamic Structure of the TIM23 Complex in the Mitochondrial Intermembrane Space

Bajaj, Rakhi; Jaremko, Łukasz; Jaremko, Mariusz; Becker, Stefan; Zweckstetter, Markus

doi:10.1016/j.str.2014.07.015

Cited by 23 publications

(22 citation statements)

References 53 publications

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“…Proteins destined for the matrix initially enter mitochondria via the TOM complex of the outer membrane, and are then translocated across the inner membrane into the matrix through the Tim17/23 translocon (Endo and Yamano, 2009; Schmidt et al, 2010). Most matrix-bound proteins are synthesized as preproteins with a positively charged amino-terminal targeting sequence (presequence), which interacts sequentially with ‘receptor’ proteins in transit from the cytosol to the inner membrane translocon (Bajaj et al, 2014; Lytovchenko et al, 2013; Marom et al, 2011b; Shiota et al, 2011). Upon insertion of the presequence into the translocon, it is driven into the matrix by the membrane potential across the inner membrane.…”

Section: Introductionmentioning

confidence: 99%

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Ting

Yan

Schilke

et al. 2017

eLife

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Proteins destined for the mitochondrial matrix are targeted to the inner membrane Tim17/23 translocon by their presequences. Inward movement is driven by the matrix-localized, Hsp70-based motor. The scaffold Tim44, interacting with the matrix face of the translocon, recruits other motor subunits and binds incoming presequence. The basis of these interactions and their functional relationships remains unclear. Using site-specific in vivo crosslinking and genetic approaches in Saccharomyces cerevisiae, we found that both domains of Tim44 interact with the major matrix-exposed loop of Tim23, with the C-terminal domain (CTD) binding Tim17 as well. Results of in vitro experiments showed that the N-terminal domain (NTD) is intrinsically disordered and binds presequence near a region important for interaction with Hsp70 and Tim23. Our data suggest a model in which the CTD serves primarily to anchor Tim44 to the translocon, whereas the NTD is a dynamic arm, interacting with multiple components to drive efficient translocation.DOI: http://dx.doi.org/10.7554/eLife.23609.001

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Section: Introductionmentioning

confidence: 99%

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Ting

Yan

Schilke

et al. 2017

eLife

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“…Several Tom and Tim proteins participate in the formation of TOM‐TIM23 translocation contact sites: the intermembrane space domain of the receptor Tom22, Tom40, and Tom7 of the outer membrane translocase, as well as Tim50, Tim23, and Tim21 of the inner membrane translocase [Fig. (A)].…”

Section: Tom‐tim Contact Sites and The Presequence Pathwaymentioning

confidence: 99%

“…Electron cryotomography shows that the contact sites are connected via protein–protein interactions, not via direct contact of the lipid phases of the membranes . The high resolution structures of various hydrophilic import components and domains have been determined and provided important information on the recognition of presequences, function of cochaperones and processing of preproteins . However, high resolution structures of the membrane domains (channels) of TOM and TIM complexes are lacking so far.…”

Section: Tom‐tim Contact Sites and The Presequence Pathwaymentioning

confidence: 99%

“…The channels formed by the TOM and TIM23 translocases are so narrow that folded proteins cannot pass [98][99][100][101][102] and thus preproteins have to be translocated in an unfolded conformation. 29,41,[103][104][105][106][107][108][109][110][111][112][113] Several Tom and Tim proteins participate in the formation of TOM-TIM23 translocation contact sites: the intermembrane space domain of the receptor Tom22, Tom40, and Tom7 of the outer membrane translocase, 88,96,[114][115][116] as well as Tim50, Tim23, and Tim21 of the inner membrane translocase 85,86,89,95,97,117,118 [Fig. 2(A)].…”

Section: Tom-tim Contact Sites and The Presequence Pathwaymentioning

confidence: 99%

“…168 The high resolution structures of various hydrophilic import components and domains have been determined and provided important information on the recognition of presequences, function of cochaperones and processing of preproteins. 48,114,116,123,131,149,[169][170][171][172][173][174][175] However, high resolution structures of the membrane domains (channels) of TOM and TIM complexes are lacking so far. This is a major reason that despite a wealth of knowledge on individual reaction steps, the exact mechanisms of preprotein translocation and the complete TOM-TIM23-PAM reaction cycle have not been elucidated yet.…”

Section: Tom-tim Contact Sites and The Presequence Pathwaymentioning

confidence: 99%

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Role of membrane contact sites in protein import into mitochondria

et al. 2015

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Mitochondria import more than 1,000 different proteins from the cytosol. The proteins are synthesized as precursors on cytosolic ribosomes and are translocated by protein transport machineries of the mitochondrial membranes. Five main pathways for protein import into mitochondria have been identified. Most pathways use the translocase of the outer mitochondrial membrane (TOM) as the entry gate into mitochondria. Depending on specific signals contained in the precursors, the proteins are subsequently transferred to different intramitochondrial translocases. In this article, we discuss the connection between protein import and mitochondrial membrane architecture. Mitochondria possess two membranes. It is a longstanding question how contact sites between outer and inner membranes are formed and which role the contact sites play in the translocation of precursor proteins. A major translocation contact site is formed between the TOM complex and the presequence translocase of the inner membrane (TIM23 complex), promoting transfer of presequence-carrying preproteins to the mitochondrial inner membrane and matrix. Recent findings led to the identification of contact sites that involve the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. MICOS plays a dual role. It is crucial for maintaining the inner membrane cristae architecture and forms contacts sites to the outer membrane that promote translocation of precursor proteins into the intermembrane space and outer membrane of mitochondria. The view is emerging that the mitochondrial protein translocases do not function as independent units, but are embedded in a network of interactions with machineries that control mitochondrial activity and architecture.

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The TIM23 mitochondrial protein import complex: function and dysfunction

Demishtein-Zohary

Azem

2016

Cell Tissue Res

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Mitochondria acquire the majority of their proteins from the cytosol in a process that is mediated by intricate multimeric machineries designed to allow proteins to cross and/or to insert themselves into the two mitochondrial membranes. Ongoing studies carried out in yeast over the past few decades have led to the discovery of numerous protein components that constitute several mitochondrial translocases. One of these complexes, the mitochondrial TIM23, is the major translocase for matrix proteins and is the focus of this review. The components of the TIM23 complex are categorized into four functional types. The first type plays the role of receptor for preproteins in the intermembrane space. The second type forms the actual channel that allows proteins to cross the inner mitochondrial membrane. The third species functions as part of the motor that mediates the final steps of import across the inner membrane. Additional components play regulatory roles orchestrating the action of this myriad of subunits. Recent studies provide new insights into the function of the mammalian TIM23 complex and the role that it plays under pathological conditions.

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Molecular Basis of the Dynamic Structure of the TIM23 Complex in the Mitochondrial Intermembrane Space

Cited by 23 publications

References 53 publications

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

Role of membrane contact sites in protein import into mitochondria

The TIM23 mitochondrial protein import complex: function and dysfunction

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