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BBA - Molecular Cell Research (v.1803, #6)
Molecular chaperones and intracellular protein transport
by Peter Rehling; Sabine Rospert (pp. 639-640).
Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility by Pablo C. Echeverria; Didier Picard (pp. 641-649).
Steroid hormone receptors (SHRs) are notorious intracellular travellers, transiting among different cellular compartments as they mature, are subjected to regulation and exert their biological functions. Understanding the processes governing the intracellular traffic of SHRs is important, since their unbalanced or erroneous localization could lead to the development of diseases. In this review, we not only explore the functions of the heat-shock protein 90 (Hsp90) molecular chaperone machine for the intracellular transport of SHRs, but also for the regulation of their nuclear mobility, for their recycling and for the regulation of their transcriptional output.
Keywords: Chaperone; Co-chaperone; Steroid hormone receptor; Hsp90; Nucleocytoplasmic shuttling; Signaling
Structure and function of the molecular chaperone Trigger Factor by Anja Hoffmann; Bernd Bukau; Günter Kramer (pp. 650-661).
Newly synthesized proteins often require the assistance of molecular chaperones to efficiently fold into functional three-dimensional structures. At first, ribosome-associated chaperones guide the initial folding steps and protect growing polypeptide chains from misfolding and aggregation. After that folding into the native structure may occur spontaneously or require support by additional chaperones which do not bind to the ribosome such as DnaK and GroEL. Here we review the current knowledge on the best-characterized ribosome-associated chaperone at present, the Escherichia coli Trigger Factor. We describe recent progress on structural and dynamic aspects of Trigger Factor's interactions with the ribosome and substrates and discuss how these interactions affect co-translational protein folding. In addition, we discuss the newly proposed ribosome-independent function of Trigger Factor as assembly factor of multi-subunit protein complexes. Finally, we cover the functional cooperation between Trigger Factor, DnaK and GroEL in folding of cytosolic proteins and the interplay between Trigger Factor and other ribosome-associated factors acting in enzymatic processing and translocation of nascent polypeptide chains.
Keywords: Chaperone; Ribosome; Protein folding; Nascent chain; Trigger Factor
The ribosome-bound Hsp70 homolog Ssb of Saccharomyces cerevisiae by Kristin Peisker; Marco Chiabudini; Sabine Rospert (pp. 662-672).
The Hsp70 homolog Ssb directly binds to the ribosome and contacts a variety of newly synthesized polypeptide chains as soon as they emerge from the ribosomal exit tunnel. For this reason a general role of Ssb in the de novo folding of newly synthesized proteins is highly suggestive. However, for more than a decade client proteins which require Ssb for proper folding have remained elusive. It was therefore speculated that Ssb, despite its ability to interact with a large variety of nascent polypeptides, may assist the folding of only a small and specific subset. Alternatively, it has been suggested that Ssb's function may be limited to the protection of nascent polypeptides from aggregation until downstream chaperones take over and actively fold their substrates. There is also evidence that Ssb, in parallel to a classical chaperone function, is involved in the regulation of cellular signaling processes. Here we aim to summarize what is currently known about Ssb's multiple functions and what remains to be ascertained by future research.
Keywords: Chaperones; Hsp70; Ribosome; Protein folding; SNF1; Signaling; Translation; Translational fidelity; Saccharomyces cerevisiae
Driving ribosome assembly by Dieter Kressler; Ed Hurt; Jochen Baβler (pp. 673-683).
Ribosome biogenesis is a fundamental process that provides cells with the molecular factories for cellular protein production. Accordingly, its misregulation lies at the heart of several hereditary diseases (e.g., Diamond-Blackfan anemia). The process of ribosome assembly comprises the processing and folding of the pre-rRNA and its concomitant assembly with the ribosomal proteins. Eukaryotic ribosome biogenesis relies on a large number (>200) of non-ribosomal factors, which confer directionality and accuracy to this process. Many of these non-ribosomal factors fall into different families of energy-consuming enzymes, notably including ATP-dependent RNA helicases, AAA-ATPases, GTPases, and kinases. Ribosome biogenesis is highly conserved within eukaryotic organisms; however, due to the combination of powerful genetic and biochemical methods, it is best studied in the yeast Saccharomyces cerevisiae. This review summarizes our current knowledge on eukaryotic ribosome assembly, with particular focus on the molecular role of the involved energy-consuming enzymes.
Keywords: Ribosome assembly; Nuclear export of ribosomes; Diamond-Blackfan anemia; Shwachman-Diamond syndrome; Dyskeratosis congenita; Cartilage–hair hypoplasia; Bowen-Conradi syndrome; Cancer; Quality control of ribosomes
Lectin chaperones help direct the maturation of glycoproteins in the endoplasmic reticulum by Bradley R. Pearse; Daniel N. Hebert (pp. 684-693).
Eukaryotic secretory pathway cargo fold to their native structures within the confines of the endoplasmic reticulum (ER). To ensure a high degree of folding fidelity, a multitude of covalent and noncovalent constraints are imparted upon nascent proteins. These constraints come in the form of topological restrictions or membrane tethers, covalent modifications, and interactions with a series of molecular chaperones. N-linked glycosylation provides inherent benefits to proper folding and creates a platform for interactions with specific chaperones and Cys modifying enzymes. Recent insights into this timeline of protein maturation have revealed mechanisms for protein glycosylation and iterative targeting of incomplete folding intermediates, which provides nurturing interactions with molecular chaperones that assist in the efficient maturation of proteins in the eukaryotic secretory pathway.
Keywords: Endoplasmic reticulum; Protein folding; Carbohydrates; Molecular chaperones; Quality control
Endoplasmic reticulum associated protein degradation: A chaperone assisted journey to hell by Alexandra Stolz; Dieter H. Wolf (pp. 694-705).
Recognition and elimination of misfolded proteins are essential cellular processes. More than thirty percent of the cellular proteins are proteins of the secretory pathway. They fold in the lumen or membrane of the endoplasmic reticulum from where they are sorted to their site of action. The folding process, as well as any refolding after cell stress, depends on chaperone activity. In case proteins are unable to acquire their native conformation, chaperones with different substrate specificity and activity guide them to elimination. For most misfolded proteins of the endoplasmic reticulum this requires retro-translocation to the cytosol and polyubiquitylation of the misfolded protein by an endoplasmic reticulum associated machinery. Thereafter ubiquitylated proteins are guided to the proteasome for degradation. This review summarizes our up to date knowledge of chaperone classes and chaperone function in endoplasmic reticulum associated degradation of protein waste.
Keywords: Chaperone; ERAD; Lectin; Protein disulfide isomerase; Hsp70; Hsp40
Transport of proteins across or into the mitochondrial outer membrane by Toshiya Endo; Koji Yamano (pp. 706-714).
Mitochondria are surrounded by two biological membranes. The outer mitochondrial membrane contains two major translocators, the TOM40 (TOM) and TOB/SAM complexes for protein translocation across and/or insertion into the outer membrane. The TOM40 complex functions as an entry gate for most mitochondrial proteins, and the TOB/SAM complex as a specialized insertion machinery for β-barrel membrane proteins. In order to handle loosely folded or unfolded precursor polypeptides, those translocators cooperate with chaperones in the cytosol and intermembrane space, and also exhibit chaperone-like functions on their own. Several α-helical membrane proteins take ‘non-standard’ routes to be inserted into the outer membrane. Here we review the current view on a remarkable variety of mechanisms of protein transport taking place at the mitochondrial outer membrane.
Keywords: Protein import; Mitochondria; Outer membrane; Chaperone; Translocator; Receptor
The TOC complex: Preprotein gateway to the chloroplast by Andres Charles Andrès; Birgit Agne; Felix Kessler (pp. 715-723).
Photosynthetic eukaryotes strongly depend on chloroplast metabolic pathways. Most if not all involve nuclear encoded proteins. These are synthesized as cytosolic preproteins with N-terminal, cleavable targeting sequences (transit peptide). Preproteins are imported by a major pathway composed of two proteins complexes: TOC and TIC ( Translocon of the Outer and Inner membranes of the Chloroplasts, respectively). These selectively recognize the preproteins and facilitate their transport across the chloroplast envelope. The TOC core complex consists of three types of components, each belonging to a small family: Toc34, Toc75 and Toc159. Toc34 and Toc159 isoforms represent a subfamily of the GTPase superfamily. The members of the Toc34 and Toc159 subfamily act as GTP-dependent receptors at the chloroplast surface and distinct members of each occur in defined, substrate-specific TOC complexes. Toc75, a member of the Omp85 family, is conserved from prokaryotes and functions as the unique protein-conducting channel at the outer membrane. In this review we will describe the current state of knowledge regarding the composition and function of the TOC complex.
Keywords: Protein targeting; Chloroplast; Preprotein; Translocon
Peroxisomal protein translocation by Wolfgang Girzalsky; Delia Saffian; Ralf Erdmann (pp. 724-731).
Peroxisomes perform a wide variety of metabolic processes in eukaryotic organisms. Mutations that affect peroxisome function or formation have profound phenotypic consequences, the latter demonstrated by peroxisome biogenesis disorders which are often fatal. The biogenesis of peroxisomes conceptually consists of: (1) the formation of the peroxisomal membrane, (2) the import of peroxisomal matrix enzymes and (3) the proliferation of the organelles. Proteins involved in these processes are collectively called peroxins, encoded by PEX-genes. To date 32 peroxins are known, which perform functions in peroxisome biogenesis that are conserved from yeast to man. In this article, we focus on the current status of knowledge about the topogenesis of the peroxisomal membrane proteins, and the import of proteins into the peroxisomal matrix.
Keywords: Abbreviations; AAA; ATPase associated with various cellular activities; ERAD; endoplasmatic reticulum associated degradation; PTS; peroxisomal targeting signal; RADAR; Receptor Accumulation and Degradation in Absence of Recycling; RING; really interesting new gene; Ub; ubiquitinPeroxisome biogenesis; Protein targeting; PEX; Peroxin; Ubiquitination; AAA ATPase
On the mechanism of preprotein import by the mitochondrial presequence translocase by Martin van der Laan; Dana P. Hutu; Peter Rehling (pp. 732-739).
Mitochondria are organelles of endosymbiontic origin that contain more than one thousand different proteins. The vast majority of these proteins is synthesized in the cytosol and imported into one of four mitochondrial subcompartments: outer membrane, intermembrane space, inner membrane and matrix. Several import pathways exist and are committed to different classes of precursor proteins. The presequence translocase of the inner mitochondrial membrane (TIM23 complex) mediates import of precursor proteins with cleavable amino-terminal presequences. Presequences direct precursors across the inner membrane. The combination of this presequence with adjacent regions determines if a precursor is fully translocated into the matrix or laterally sorted into the inner mitochondrial membrane. The membrane-embedded TIM23SORT complex mediates the membrane potential-dependent membrane insertion of precursor proteins with a stop-transfer sequence downstream of the mitochondrial targeting signal. In contrast, translocation of precursor proteins into the matrix requires the recruitment of the presequence translocase-associated motor (PAM) to the TIM23 complex. This ATP-driven import motor consists of mitochondrial Hsp70 and several membrane-associated co-chaperones. These two structurally and functionally distinct forms of the TIM23 complex (TIM23SORT and TIM23MOTOR) are in a dynamic equilibrium with each other. In this review, we discuss recent advances in our understanding of the mechanisms of matrix translocation and membrane insertion by the TIM23 machinery.
Keywords: Mitochondria; Presequence translocase; TIM23 complex; Import motor; Respiratory chain
Protein import into chloroplasts: The Tic complex and its regulation by Kovacs-Bogdan Erika Kovács-Bogdán; Jürgen Soll; Bolter Bettina Bölter (pp. 740-747).
Chloroplasts like mitochondria were derived from an endosymbiontic event. Due to the massive gene transfer to the nucleus during endosymbiosis, only a limited number of chloroplastic proteins are still encoded for in the plastid genome. Most of the nuclear-encoded plastidic proteins are post-translationally translocated back to the chloroplast via the general import pathway through distinct outer and inner envelope membrane protein complexes, the Toc and Tic translocons ( Translocon at the outer/ inner envelope membrane of chloroplasts). Eight Tic subunits have been described so far, including two potential channel proteins (Tic110 and Tic20), the “motor complex” (Tic40 associated with the stromal chaperone Hsp93) and the “redox regulon” (Tic62, Tic55, and Tic32) involved in regulation of protein import via the metabolic redox status of the chloroplast. Regulation can additionally occur via thioredoxins (Tic110 and Tic55) or via the calcium/calmodulin network (Tic110 and Tic32). In this review we present the current knowledge about the Tic complex focusing on its regulation and addressing some still open questions.
Keywords: Abbreviations; CaM; calmodulin; Clp; caseinolytic protease; DEPC; diethylpyrocarbonate; FNR; ferredoxin-NADP; +; -oxidoreductase; Hip; Hsp70 interacting protein; Hop; Hsp70 and Hsp90 organizing protein; PAO; pheophorbide a oxygenase; Tic; translocon at the inner envelope membrane of chloroplasts; Toc; translocon at the outer envelope membrane of chloroplasts; TPR; tetratricopeptide repeat; Trx; thioredoxinCalcium/calmodulin; Chloroplast; Endosymbiosis; Protein import; Redox regulation; Tic complex
Biogenesis of membrane bound respiratory complexes in Escherichia coli by Claire E. Price; Arnold J.M. Driessen (pp. 748-766).
Escherichia coli is one of the preferred bacteria for studies on the energetics and regulation of respiration. Respiratory chains consist of primary dehydrogenases and terminal reductases or oxidases linked by quinones. In order to assemble this complex arrangement of protein complexes, synthesis of the subunits occurs in the cytoplasm followed by assembly in the cytoplasm and/or membrane, the incorporation of metal or organic cofactors and the anchoring of the complex to the membrane. In the case of exported metalloproteins, synthesis, assembly and incorporation of metal cofactors must be completed before translocation across the cytoplasmic membrane. Coordination data on these processes is, however, scarce. In this review, we discuss the various processes that respiratory proteins must undergo for correct assembly and functional coupling to the electron transport chain in E. coli. Targeting to and translocation across the membrane together with cofactor synthesis and insertion are discussed in a general manner followed by a review of the coordinated biogenesis of individual respiratory enzyme complexes. Lastly, we address the supramolecular organization of respiratory enzymes into supercomplexes and their localization to specialized domains in the membrane.
Keywords: YidC; SecYEG; SecA; Tat; Respiration; ATP synthase
Co-translational membrane insertion of mitochondrially encoded proteins by Martin Ott; Johannes M. Herrmann (pp. 767-775).
The components of the mitochondrial proteome represent a mosaic of dual genetic origin: while most mitochondrial proteins are encoded by nuclear genes and imported into the organelle following synthesis in the cytosol, a small number of proteins is encoded by the mitochondrial genome. Though small in number, mitochondrial translation products are vital for cellular functionality as these proteins represent the core subunits of the respiratory chain and the ATPase which produce the vast majority of the cellular ATP. Mitochondrial translation products are almost exclusively highly hydrophobic polypeptides which are inserted into the inner membrane in the course of their synthesis. The machinery that mediates membrane insertion in mitochondria is deduced from that of their bacterial ancestors and hence shows profound similarities to the insertion machinery of prokaryotes. However, the specialization on the production of a very small set of translation products drove a severe reduction in the complexity of this system. The insertase Oxa1 forms the central component of the insertion machinery. Oxa1 directly binds to mitochondrial ribosomes and, together with the inner membrane protein Mba1, aligns the polypeptide exit tunnel of the ribosome with the insertion site at the inner membrane. The specific hallmarks and the critical components of this machinery are discussed in this review article.
Keywords: Membrane biogenesis; Mitochondrion; Oxa1; Respiratory chain; Ribosome