Glycine-Rich Loop of Mitochondrial Processing Peptidase α-Subunit Is Responsible for Substrate Recognition by a Mechanism Analogous to Mitochondrial Receptor Tom20

Dvoráková-Holá, Klára; Matušková, Anna; Kubala, Martin; Otyepka, Michal; Kučera, Tomáš; Večeř, Jaroslav; Heřman, Petr; Parkhomenko, N. T.; Kutějová, Eva; Janata, Jiřı́

doi:10.1016/j.jmb.2009.12.054

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…PMPCB, also known as β-MPP, is the main peptidase responsible for cleaving the mitochondrial import signal from hundreds of mitochondrial proteins 16 . The mitochondrial processing peptidase (MPP) complex is localized in the mitochondrial matrix, forming a heterodimer composed of PMPCB and its non-protease homologue PMPCA 17 , which recognizes and binds the presequences of imported proteins, thereby facilitating subsequent proteolytic processing by PMPCB 18 . The processing peptidases mitochondrial inner membrane protease subunit 1 (IMMP1L) and IMMP2L remove hydrophobic sorting signals from proteins that are sorted to the intermembrane space, often after these proteins have been processed by MPPs 19 .…”

Section: New and Emerging Roles Of Mitoproteasesmentioning

confidence: 99%

New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

456

424

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Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.

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Section: New and Emerging Roles Of Mitoproteasesmentioning

confidence: 99%

New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

456

424

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“…Furthermore, the process of α-helix loop folding was accompanied by reorientation of the N-terminus of the substrate towards the enzyme active site. Thus, although initially we hypothesized that hydrophobic interactions play an important role only during the initial substrate recognition [17], now it seems to be likely that hydrophobic interactions take significant part also later during the substrate translocation process.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the deletion of G292 makes α-MPP alone unable to bind (i.e. recognize) the short presequence of yeast MDH [17]. …”

Section: Discussionmentioning

confidence: 99%

“…The most conserved part of all known α-MPPs is the glycine-rich loop (GRL; residues G 285 GGSFSAGGPGKGMYS 300 in the yeast α-MPP), which has been shown to be essential for substrate binding [16]. The GRL also seems to be the structural element where the initial interaction between MPP and the signal presequence occurs [17]. The most important role in this process may be a hydrophobic interaction between two residues on one side of the presequence α-helix (often in positions -4 and +1, with respect to the cleavage site) with M298 and Y303 of the GRL.…”

Section: Introductionmentioning

confidence: 99%

“…Although the MPP crystal structure was published more than a decade ago [4], very few studies have addressed the detailed operation of MPP. To date, the substrate binding and cleavage mechanism in the MPP active site (AS) has been described in detail [19] ( AS-bound structure in Figure 1) and a mechanism of substrate recognition by the GRL has been outlined [17] ( GRL-bound structure in Figure 1), however the mechanism of substrate translocation from the GRL to the MPP active site has not yet been investigated. Since the whole process is complex and involves interactions of larger regions rather than single amino acids, the experimental approach using amino acid point mutations is problematic.…”

Section: Introductionmentioning

confidence: 99%

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A Computational Study of the Glycine-Rich Loop of Mitochondrial Processing Peptidase

et al. 2013

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An all atomic, non-restrained molecular dynamics (MD) simulation in explicit water was used to study in detail the structural features of the highly conserved glycine-rich loop (GRL) of the α-subunit of the yeast mitochondrial processing peptidase (MPP) and its importance for the tertiary and quaternary conformation of MPP. Wild-type and GRL-deleted MPP structures were studied using non-restrained MD simulations, both in the presence and the absence of a substrate in the peptidase active site. Targeted MD simulations were employed to study the mechanism of substrate translocation from the GRL to the active site. We demonstrate that the natural conformational flexibility of the GRL is crucial for the substrate translocation process from outside the enzyme towards the MPP active site. We show that the α-helical conformation of the substrate is important not only during its initial interaction with MPP (i.e. substrate recognition), but also later, at least during the first third of the substrate translocation trajectory. Further, we show that the substrate remains in contact with the GRL during the whole first half of the translocation trajectory and that hydrophobic interactions play a major role. Finally, we conclude that the GRL acts as a precisely balanced structural element, holding the MPP subunits in a partially closed conformation regardless the presence or absence of a substrate in the active site.

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Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Glycine-Rich Loop of Mitochondrial Processing Peptidase α-Subunit Is Responsible for Substrate Recognition by a Mechanism Analogous to Mitochondrial Receptor Tom20

Cited by 22 publications

References 39 publications

New roles for mitochondrial proteases in health, ageing and disease

New roles for mitochondrial proteases in health, ageing and disease

A Computational Study of the Glycine-Rich Loop of Mitochondrial Processing Peptidase

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

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