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Biochimica Et Biophysica Acta May 2016Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent... (Review)
Review
Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent discovery, several studies have highlighted key mechanistic details of the pathway. The endoplasmic reticulum (ER) is the primary source of lipids and proteins for the newly-formed peroxisomes. More recently, an intricate sorting process functioning at the ER has been proposed, that segregates specific PMPs first to peroxisome-specific ER domains (pER) and then assembles PMPs selectively into distinct pre-peroxisomal vesicles (ppVs) that later fuse to form import-competent peroxisomes. In addition, plausible roles of the three key peroxins Pex3, Pex16 and Pex19, which are also central to the growth and division pathway, have been suggested in the de novo process. In this review, we discuss key developments and highlight the unexplored avenues in de novo peroxisome biogenesis.
Topics: Animals; Endoplasmic Reticulum; Eukaryotic Cells; Fungal Proteins; Gene Expression Regulation; Humans; Membrane Proteins; Organelle Biogenesis; Peroxins; Peroxisomes; Plants; Protein Isoforms; Protein Structure, Tertiary; Protein Transport; Saccharomyces cerevisiae Proteins; Signal Transduction; Yeasts
PubMed: 26381541
DOI: 10.1016/j.bbamcr.2015.09.014 -
The Protein Journal Jun 2019More than 2500 nuclear encoded preproteins are required for the function of chloroplasts in terrestrial plants. These preproteins are imported into chloroplasts via the... (Review)
Review
More than 2500 nuclear encoded preproteins are required for the function of chloroplasts in terrestrial plants. These preproteins are imported into chloroplasts via the concerted action of two multi-subunit translocons of the outer (TOC) and inner (TIC) membranes of the chloroplast envelope. This general import machinery functions to recognize and import proteins with high fidelity and efficiency to ensure that organelle biogenesis is properly coordinated with developmental and physiological events. Two components of the TOC machinery, Toc34 and Toc159, act as the primary receptors for preproteins at the chloroplast surface. They interact with the intrinsic targeting signals (transit peptides) of preproteins to mediate the selectivity of targeting, and they contribute to the quality control of import by constituting a GTP-dependent checkpoint in the import reaction. The TOC receptor family has expanded to regulate the import of distinct classes of preproteins that are required for remodeling of organelle proteomes during plastid-type transitions that accompany developmental changes. As such, the TOC receptors function as central regulators of the fidelity, specificity and selectivity of the general import machinery, thereby contributing to the integration of protein import with plastid biogenesis.
Topics: Arabidopsis; Arabidopsis Proteins; Chloroplasts; GTP Phosphohydrolases; Membrane Transport Proteins; Protein Transport
PubMed: 31201619
DOI: 10.1007/s10930-019-09846-3 -
Nature Nov 2019The translocase of the outer mitochondrial membrane (TOM) is the main entry gate for proteins. Here we use cryo-electron microscopy to report the structure of the yeast...
The translocase of the outer mitochondrial membrane (TOM) is the main entry gate for proteins. Here we use cryo-electron microscopy to report the structure of the yeast TOM core complex at 3.8-Å resolution. The structure reveals the high-resolution architecture of the translocator consisting of two Tom40 β-barrel channels and α-helical transmembrane subunits, providing insight into critical features that are conserved in all eukaryotes. Each Tom40 β-barrel is surrounded by small TOM subunits, and tethered by two Tom22 subunits and one phospholipid. The N-terminal extension of Tom40 forms a helix inside the channel; mutational analysis reveals its dual role in early and late steps in the biogenesis of intermembrane-space proteins in cooperation with Tom5. Each Tom40 channel possesses two precursor exit sites. Tom22, Tom40 and Tom7 guide presequence-containing preproteins to the exit in the middle of the dimer, whereas Tom5 and the Tom40 N extension guide preproteins lacking a presequence to the exit at the periphery of the dimer.
Topics: Cryoelectron Microscopy; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Models, Molecular; Phospholipids; Protein Multimerization; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 31600774
DOI: 10.1038/s41586-019-1680-7 -
Science China. Life Sciences Oct 2020Mammalian mitochondria have small genomes encoding very limited numbers of proteins. Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be...
Mammalian mitochondria have small genomes encoding very limited numbers of proteins. Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria. Here, we report the identification of hundreds of circular RNAs (mecciRNAs) encoded by the mitochondrial genome. We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins. Known components involved in mitochondrial protein and RNA importation, such as TOM40 and PNPASE, interact with mecciRNAs and regulate protein entry. The expression of mecciRNAs is regulated, and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation. mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus.
Topics: Animals; Cell Nucleus; Gene Expression; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Mice; Mitochondria; Molecular Chaperones; Protein Binding; Protein Transport; RNA, Circular; RNA, Mitochondrial; Replication Protein A; Zebrafish
PubMed: 32048164
DOI: 10.1007/s11427-020-1631-9 -
Biochemistry and Cell Biology =... Dec 2014Mitochondrial ribosomes of baker's yeast contain at least 78 protein subunits. All but one of these proteins are nuclear-encoded, synthesized on cytosolic ribosomes, and... (Review)
Review
Mitochondrial ribosomes of baker's yeast contain at least 78 protein subunits. All but one of these proteins are nuclear-encoded, synthesized on cytosolic ribosomes, and imported into the matrix for biogenesis. The import of matrix proteins typically relies on N-terminal mitochondrial targeting sequences that form positively charged amphipathic helices. Interestingly, the N-terminal regions of many ribosomal proteins do not closely match the characteristics of matrix targeting sequences, suggesting that the import processes of these proteins might deviate to some extent from the general import route. So far, the biogenesis of only two ribosomal proteins, Mrpl32 and Mrp10, was studied experimentally and indeed showed surprising differences to the import of other preproteins. In this review article we summarize the current knowledge on the transport of proteins into the mitochondrial matrix, and thereby specifically focus on proteins of the mitochondrial ribosome.
Topics: Mitochondria; Protein Transport; Ribosomal Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 24943357
DOI: 10.1139/bcb-2014-0029 -
Trends in Biochemical Sciences Mar 2016Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX9C) type motifs are imported into the mitochondrion with the... (Review)
Review
Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX9C) type motifs are imported into the mitochondrion with the help of the disulfide relay-dependent MIA import pathway. These evolutionarily conserved proteins are emerging as new cellular factors that control mitochondrial respiration, redox regulation, lipid homeostasis, and membrane ultrastructure and dynamics. We discuss recent insights on the activity of known (CX9C) motif-carrying proteins in mammals and review current data implicating the Mia40/CHCHD4 import machinery in the regulation of their mitochondrial import. Recent findings and the identification of disease-associated mutations in specific (CX9C) motif-carrying proteins have highlighted members of this family of proteins as potential therapeutic targets in a variety of human disorders.
Topics: Mitochondrial Proteins; Protein Conformation
PubMed: 26782138
DOI: 10.1016/j.tibs.2015.12.004 -
Biochemical and Biophysical Research... Oct 2019Preprotein import into chloroplasts is mediated by the coordinated actions of translocons at the outer and inner envelopes of chloroplasts (Toc and Tic, respectively)....
Preprotein import into chloroplasts is mediated by the coordinated actions of translocons at the outer and inner envelopes of chloroplasts (Toc and Tic, respectively). The cleavable N-terminal transit peptide (TP) of preproteins plays an essential role in the import of preproteins into chloroplasts. The Tic40 protein, a component of the Tic complex, is believed to mediate the import of preproteins through the inner envelope. In this study, we aimed to obtain in vivo evidence supporting the role of Tic40 in preprotein import into chloroplasts. Contrary to previous findings, the import of various preproteins with wild-type TPs showed no difference between tic40 and wild-type protoplasts of Arabidopsis thaliana. However, the import of N-terminal mutants of the RbcS protein (RbcS-nt), in which basic amino acid residues (arginine and lysine) in the central region of the TP were substituted with neutral (alanine) or acidic (glutamic acid) amino acid residues, was dependent on Tic40. In addition, in tic40 protoplasts, the inner envelope protein Tic40 tagged with HA (hemagglutinin) showed more intermediate form present in the stroma. Based on these results, we propose that protein can be imported into chloroplast by either Tic40-independent or Tic40-dependent pathways depending on the types of TP.
Topics: Amino Acid Sequence; Amino Acids; Arabidopsis; Arabidopsis Proteins; Chloroplast Proteins; Chloroplasts; Membrane Proteins; Molecular Chaperones; Mutant Proteins; Protein Precursors; Protein Sorting Signals; Protein Transport; Solubility
PubMed: 31400859
DOI: 10.1016/j.bbrc.2019.08.009 -
Nature Communications May 2017Protein import into organelles is essential for all eukaryotes and facilitated by multi-protein translocation machineries. Analysing whether a protein is transported...
Protein import into organelles is essential for all eukaryotes and facilitated by multi-protein translocation machineries. Analysing whether a protein is transported into an organelle is largely restricted to single constituents. This renders knowledge about imported proteins incomplete, limiting our understanding of organellar biogenesis and function. Here we introduce a method that enables charting an organelle's importome. The approach relies on inducible RNAi-mediated knockdown of an essential subunit of a translocase to impair import and quantitative mass spectrometry. To highlight its potential, we established the mitochondrial importome of Trypanosoma brucei, comprising 1,120 proteins including 331 new candidates. Furthermore, the method allows for the identification of proteins with dual or multiple locations and the substrates of distinct protein import pathways. We demonstrate the specificity and versatility of this ImportOmics method by targeting import factors in mitochondria and glycosomes, which demonstrates its potential for globally studying protein import and inventories of organelles.
Topics: Amino Acyl-tRNA Synthetases; Gene Knockdown Techniques; Mass Spectrometry; Microbodies; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Protein Transport; Proteome; Protozoan Proteins; Substrate Specificity; Trypanosoma brucei brucei
PubMed: 28485388
DOI: 10.1038/ncomms15272 -
American Journal of Human Genetics May 2019Mitochondrial dysfunction has consequences not only for cellular energy output but also for cellular signaling pathways. Mitochondrial dysfunction, often based on... (Review)
Review
Mitochondrial dysfunction has consequences not only for cellular energy output but also for cellular signaling pathways. Mitochondrial dysfunction, often based on inherited gene variants, plays a role in devastating human conditions such as mitochondrial neuropathies, myopathies, cardiovascular disorders, and Parkinson and Alzheimer diseases. Of the proteins essential for mitochondrial function, more than 98% are encoded in the cell nucleus, translated in the cytoplasm, sorted based on the presence of encoded mitochondrial targeting sequences (MTSs), and imported to specific mitochondrial sub-compartments based on the integrated activity of a series of mitochondrial translocases, proteinases, and chaperones. This import process is typically dynamic; as cellular homeostasis is coordinated through communication between the mitochondria and the nucleus, many of the adaptive responses to stress depend on modulation of mitochondrial import. We here describe an emerging class of disease-linked gene variants that are found to impact the mitochondrial import machinery itself or to affect the proteins during their import into mitochondria. As a whole, this class of rare defects highlights the importance of correct trafficking of mitochondrial proteins in the cell and the potential implications of failed targeting on metabolism and energy production. The existence of this variant class could have importance beyond rare neuromuscular disorders, given an increasing body of evidence suggesting that aberrant mitochondrial function may impact cancer risk and therapeutic response.
Topics: Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Membrane Transport Proteins; Molecular Chaperones; Protein Transport
PubMed: 31051112
DOI: 10.1016/j.ajhg.2019.03.019 -
Proceedings of the National Academy of... Sep 2022IMPORTIN-4, the primary nuclear import receptor of core histones H3 and H4, binds the H3-H4 dimer and histone chaperone ASF1 prior to nuclear import. However, how...
IMPORTIN-4, the primary nuclear import receptor of core histones H3 and H4, binds the H3-H4 dimer and histone chaperone ASF1 prior to nuclear import. However, how H3-H3-ASF1 is recognized for transport cannot be explained by available crystal structures of IMPORTIN-4-histone tail peptide complexes. Our 3.5-Å IMPORTIN-4-H3-H4-ASF1 cryoelectron microscopy structure reveals the full nuclear import complex and shows a binding mode different from suggested by previous structures. The N-terminal half of IMPORTIN-4 clamps the globular H3-H4 domain and H3 αN helix, while its C-terminal half binds the H3 N-terminal tail weakly; tail contribution to binding energy is negligible. ASF1 binds H3-H4 without contacting IMPORTIN-4. Together, ASF1 and IMPORTIN-4 shield nucleosomal H3-H4 surfaces to chaperone and import it into the nucleus where RanGTP binds IMPORTIN-4, causing large conformational changes to release H3-H4-ASF1. This work explains how full-length H3-H4 binds IMPORTIN-4 in the cytoplasm and how it is released in the nucleus.
Topics: Cell Nucleus; Cryoelectron Microscopy; Cytoplasm; Histone Chaperones; Histones; Humans; Karyopherins; Membrane Transport Proteins; Molecular Chaperones; Protein Conformation; Protein Multimerization; Saccharomyces cerevisiae Proteins
PubMed: 36103578
DOI: 10.1073/pnas.2207177119