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27.3: Translational Regulation and Protein Degradation

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    15203
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    Search Fundamentals of Biochemistry

    Regulation of Translation

    Heterogeneity of Ribosome Structure

    Over the years, many studies performed in eukaryotes presented evidence that ribosomes can vary in their protein and rRNA complement between different cell types and developmental states. These observations culminated in the postulation of the ‘ribosome filter hypothesis’ by Mauro and Edelman in the year 2002. The authors propose that the ribosome composition functions as translation determination factor. Depending on the RPs and rRNA sequences represented in the respective ribosome, the complex acts like a filter that selects for specific mRNAs and hence modulates translation, as shown in Figure \(\PageIndex{1}\). RP heterogeneity can arise from differential expression of paralogs/homologs of RP proteins within different cell types or occur due to differential post-translational modifications of RPs, such as phosphorylation. The protein to rRNA ratio may also slightly vary within ribosomal composition affecting translation efficiency and selectivity.

    https://ars.els-cdn.com/content/image/1-s2.0-S0300908414003952-gr2_lrg.jpg
    Figure \(\PageIndex{1}\): Components of the translation machinery that have the potential to contribute to functional heterogeneity. Structures were visualized with Polyview 3D software using the following maps: E. coli large ribosomal subunit (LSU; pdb accession code: 3d5a, rRNA in light gray, proteins in dark gray); small ribosomal subunit (SSU; pdb accession code: 3d5b); E. coli IF2 (pdb accession code: 1g7r); human eIF3 (EMD-2166); yeast tRNAPhe (pdb accession code: 6tna).Sauert, M., Temmel, H., and Moll, I. (2015) Biochimie 114: 39-47.

    RNA genes are also present in multiple copies throughout the genomes of organisms from all domains of life. For example, the bacteria Streptomyces coelicolor harbors six copies of divergent large subunit (LSU) rRNA genes that constitute at least five different LSU rRNA species in a cell. These genes were shown to be differentially transcribed during the morphological development of the organism. Similarly, B. subtilis harbors ten rRNA operons and their reduction to one copy increased the doubling time as well as the sporulation frequency and the motility of the resulting mutant.

    Modification of the rRNA also provides another avenue of ribosomal heterogeneity. Similar to tRNA, rRNA residues can be chemically modified and commonly have 2-OH methylation. The conversion of uridine to psuedoruridine is also quite common. In eukaryotes, the modifications are facilitated by snoRNAs and their tissue specific expression might be a source for ribosome specialization. In light of the increasing evidence, ribosome heterogeneity, though still far from being entirely understood, proves to be an integral mechanism to modulate and fine tune protein synthesis in response to environmental signals in all organisms.

    Effects of Sequence and Secondary Structure in mRNA

    The amount of protein produced from any given mRNA (i.e., the translational output) is influenced by multiple factors specified by the primary nucleotide sequence. These factors include GC content, codon usage, codon pairs, and secondary structure.

    For example, 5’UTR sequences in the mRNA may interact with small miRNAs and lead to RNA interference. miRNA interactions may also target mRNA for degradation, as shown in Figure \(\PageIndex{2}\) below. This process is aided by protein chaperones called argonautes. This antisense-based process involves steps that first process the miRNA so that it can base-pair with a region of its target mRNAs. Once the base pairing occurs, other proteins direct the mRNA to be destroyed by nucleases. Fire and Mello were awarded the 2006 Nobel Prize in Physiology or Medicine for this discovery.

     

    MiRNA (1).svg

     

    Figure \(\PageIndex{2}\): Role of Micro RNA (miRNA) in the Inhibition of Eukaryotic mRNA Translation. Wikimedia Commons

    Step (1) shows how Exportin-5 transports a hairpin primary micro RNA (pri-miRNA) out of the nucleus and into the cytoplasm.

    Step (2) shows how Dicer (not shown) trims the pri-miRNA and removes the hairpin loop. A group of proteins, known as Argonautes, form a miRNA/protein complex.

    Steps (3,4) shows how miRNA/protein complex hydrogen bonds with mRNA based on complimentary sequence homology, and blocks translation.

    Step (5) shows the miRNA/protein complex binding speeds up the breakdown of the polyA tail of the mRNA, causing the mRNA to be degraded sooner.

    Effects of the Nascent Peptide on Ribosome Efficiency

    Since the Peptidyl Transferase Center (PTC) is buried within the large subunit, during translation the nascent peptide chain (NC) exits through a 100 Å long tunnel, as showin in Figure \(\PageIndex{3}\) below. The exit tunnel plays an active role in protein synthesis. Certain peptide sequences specifically interact with tunnel walls and induce ribosome stalling. Furthermore, the exit tunnel is a binding site for a clinically important class of antibiotics known as the macrolides.

    https://ars.els-cdn.com/content/image/1-s2.0-S0959440X1730132X-gr2_lrg.jpg
    Figure \(\PageIndex{3}\): The Ribosomal Exit Tunnel (a) Scheme of the ribosome exit tunnel with several proteins highlighted. NC, nascent peptide chain; ERY, erythromycin; PTC, peptidyl transferase center. (b) Context of the erythromycin (ERY, in green) binding; figure based on PDB: 5JTE. Several large subunit nucleotides are highlighted in bold red. Two proteins uL4 and uL22 form a constriction site. The nascent peptide is shown as transparent surface structure. Bock, L.V., Kolár, M.H., Grubmüller, H. (2018) Cur. Op. Struc. Bio. 49:27-35

     

    When synthesizing proteins containing proline stretches (i.e. several prolines in a row), ribosomes become stalled. Stalling is alleviated by a specialized elongation factor, EF-P in bacteria. Recently, cryo-EM structures of a ribosome stalled by a proline stretch with and without EF-P were resolved. In simulations of the PTC region, elongation factor P (EF-P) was observed to stabilize the P-site tRNA in a conformation compatible with peptide bond formation, while in the absence of EF-P, the P-site tRNA moved away from the A-site tRNA.

    The exit tunnel can accommodate 30–60 AAs, depending on the level of NC compaction. The rate of translation of about 4–22 AA per second in bacteria provides the NC with sufficient time to explore its conformational space and to start folding when still bound to the ribosome-tRNA complex.

    Proteasome

    The 26S proteasome is the central element of proteostasis regulation in eukaryotic cells. It is required for the degradation of protein factors in multiple cellular pathways and it plays a fundamental role in cell stability. The 26S proteasome has a structural configuration that confines the proteolytic active sites in a location unreachable for native and functional proteins, thus preventing uncontrolled degradation. The proteolytic active sites are found in the interior of a barrel-shaped core particle (CP or 20S). The entrances of the tunnel, placed at the distal ends of the barrel, are commonly occupied by the regulatory particle (RP or 19S), a sophisticated protein assembly that acts as a substrate processing machine. The regulatory particle has the important role of receiving, deubiquitinating, unfolding and translocating substrates to the CP and it adopts different configurations depending on the activity states they exhibit. This process typically requires ATP hydrolysis. Moreover, conformationally distinct proteasomes may show different subcellular distributions depending on functional requirements in each cellular type and environmental situations. Proteasomes are distributed throughout the cell, detected in the cytoplasm and in the nucleus, and they can localize to hotspots in distinct intracellular regions or specific sites with high protein metabolism or with specific protein degradation requirements.

    The core of the proteasome consists of a symmetrical cylinder-shaped structure composed of four stacked rings, each containing 7 different subunits and is called the 20S proteasome, as shown in Figure \(\PageIndex{4}\) below. The two outer rings are each composed of seven α-subunits (α1-α7 or PSMA1-7). During proteasome assembly, the α-rings serve as backbone for the incorporation of β-subunits, followed by dimerization of two half proteasomes. In mature proteasomes, the α-rings regulate substrate entrance since the α-subunits have hydrophobic loops that close the 20S barrel to prevent random entry of substrates.

     

    visualizeproteasomeactivityFig1.svg

    Figure \(\PageIndex{4}\): Sabine et al., Frontiers in Molecular Biosciences, 6 (2019), https://www.frontiersin.org/articles...olb.2019.00056. DOI=10.3389/fmolb.2019.00056. Creative Commons Attribution License (CC BY).

    The 20S core of the proteasome consists of 4 stacked rings. The outer rings contain seven α-subunits (white) while the inner rings contain seven β-subunits (purple). The catalytic subunits, β1, β2, and β5, are depicted in shades of blue. Gate opening of the 20S core occurs via capping by proteasome activators such as the 19S cap or PA28. The 19S cap is the most abundant activator and it forms the 26S proteasome together with the 20S core. Different cells have differnt caps. For example, interferoIFN-γ stimulation induces de novo formation of immunoproteasomes, which contains the immune subunits β1i (LMP2), β5i (LMP7), and β2i (MECL-1) (shades of red), as well as proteasome activation by PA28αβ (shades of green). Proteasome in neural tissue are discussed below..

    In general, protein entry can only be established after gate opening by proteasome activators (PAs) such as the 19S cap, after which substrates can enter the interior of the 20S core for degradation. The inner two rings of the 20S barrel consist of the subunits β1-β7 (PSMB1-7). Each β-ring contains 3 catalytic subunits; termed β1, β2, and β5. In mature 20S complexes, the pro-peptides of these catalytic β-subunits are auto-catalytically removed. Upon autocatalytic processing, the N-terminal threonine residues become exposed as the catalytically reactive residues, harboring both the nucleophile (the hydroxyl group) and the catalytic base (the N-terminal amine) involved in peptide bond cleavage. Each catalytic subunit has selectivity toward specific residues. β1 has caspase- or peptidyl-glutamyl peptidase-like activity, preferring cleavage at the C-terminus of acidic residues. β2 has trypsin-like activity and cleaves after basic residues, while β5 has chymotrypsin-like activity and prefers cleavage after hydrophobic residues

    Figure \(\PageIndex{5}\) below shows an interactive iCn3D model of the Human 20S Proteasome (6RGQ).

    Human 20S Proteasome (6RGQ).png

    Figure \(\PageIndex{5}\): Human 20S Proteasome (6RGQ). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...9gDp6nj7Co2Ud9

    The alpha subunits are shown in light gray and the beta subunits in light cyan. Active site residue, as defined by databases, are shown for one of the alpha chain (L37, Q53, K55, H68, V170) and for one of the beta chains (T1, D17, R19, K33, S130, D167, S170, G171).

    A possible generic mechanism for the cleavage of peptide bonds by the beta chain is shown in Figure \(\PageIndex{6}\) below.

     

    proteasomebetaMech.svg

    Figure \(\PageIndex{6}\): Possible mechanism for the beta chain proteasome cleavage of proteins. after Arjun Saha, Gabriel Oanca, Dibyendu Mondal, and Arieh Warshel. The Journal of Physical Chemistry B 2020124 (27), 5626-5635. DOI: 10.1021/acs.jpcb.0c04435

    The mechanism shown how the newly exposed N-terminal threonine acts as both a both the nucleophile (the hydroxyl group) and the catalytic base.

    Proteins are normally targeted to the proteasome by means of ubiquitin labels attached covalently to a lysine residue, usually in a chained form that produces a polyubiquinated protein. The process of protein polyubiquitination is carried out by a highly specialized and diverse enzymatic system, which
    includes families of ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3).

    The covalent attachment of ubiquitin to specific target proteins is mainly accomplished by stepwise enzymatic cascade reactions, and ubiquitin is attached to the substrates via the concerted action of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). The attachment of ubiquitin or ubiquitin chains to the substrate is a successive process, as shown in Figure \(\PageIndex{7}\) below. First, the C-terminal carboxylic acid is activated by adenylation using a molecule of ATP forming an adenylate (AMP-) intermediate. The adenylate acts as a good leaving group during the next reaction where an E1-ubiquitin thioester bond is formed between the C-terminal Gly carboxyl group of ubiquitin and the active site Cys of the E1 enzyme. AMP leaves the active site at this point. Note that ATP is used in many reactions to activate carboxylic acid functional groups through the formation of an adenylate intermediate and that this will be seen as a theme in many different types of reactions throughout this textbook. Once the ubiquitin is docked as a thioester on E1, it can be transferred to a Cys residue of the E2 enzyme to form an E2-ubiquitin thioester-linked intermediate. This enzymatic reaction is known as a transesterification.

    Enzymatic Activity of the E1 Ubiquitin Activating Enzyme.svg

     

    Figure \(\PageIndex{7}\): Enzymatic Activity of the E1 Ubiquitin Activating Enzyme. Conversion of Gly 76 on ubiquitin to E1 and E2 thioesters. After Hann, Z.S., et. al. (2019) PNAS 116(31)15475-15484.

    Eventually the E2 transfers the ubiquitin to the substrate protein by E3. Ubiquitin is conjugated to the target protein through an isopeptide bond between its C-terminal glycine (Gly76) and the ε-amino group of a lysine residue. There are three typical ways of linking the ubiquitin with the substrate, as shown in Figure \(\PageIndex{8}\) below. The first is called mono-ubiquitination, which refers to the modification of one site of the modification of a substrate by a single ubiquitin molecule. The second is multi-mono-ubiquitination, which means adding several ubiquitin molecules repetitively to distinct sites (multi-mono-ubiquitination). The third is called polyubiquitination (including linear polyubiquitination and branched polyubiquitination), in which ubiquitin molecules are added to the same site (polyubiquitination, including linear polyubiquitination and branched polyubiquitination) of a substrate. In the second and third ways of linking, the previously attached ubiquitin serves as the “acceptor” of subsequently added ubiquitin. Of course, polyubiquitin chains linked by the same Lys are homogeneous, while those linked at different Lys are heterogeneous or mixed ones.

    The Ubiquitin Conjugating EnzymeFig1.svg

    Figure \(\PageIndex{8}\): The Ubiquitin-Proteasome System. Liu, W., et.al. (2020) Int J Mol Sci 21(8):2894

    The process of ubiquitination from activation to attachment to the substrate is catalyzed by three major enzymes. The substrates labeled by ubiquitin are degraded by the 26S proteasome or play a non-degradative role in other processes. Abbreviations: APC, Anaphase-promoting complex; DUBs, Deubiquitinating enzymes; E1, Ubiquitin-activating enzyme; E2, Ubiquitin-conjugating enzyme; E3, Ubiquitin-ligase enzyme; Cul-based, Cullin-RING box1-Ligase; HECT, Homology to E6-AP C Terminus; Ub, Ubiqitin; SUMO, Small ubiquitin-related modifier; RBX1, RING-Box 1; RING, Really interesting new gene; RBR, RING1-IBR(cysteine/histidine rich region)-RING2.

    Subsequently, the substrate complex tagged by the ubiquitin is either degraded by the 26S proteasome or executes nonproteolytic functions, such as the regulation of gene expression, cellular trafficking, or other biological function. In most cases, polyubiquitinated proteins are recognized and degraded by the 26S proteasome, and the ubiquitin or ubiquitin chain is hydrolyzed and freed by deubiquitinating enzymes (DUBs) for reuse in further conjugation cycles after being removed from the substrate protein (Figure 27.3.6).

    The family of E3 enzymes is large and diverse. It is estimated that there are 600-700 E3 enzymes in humans, representing approximately 5% of the human genome. Thus, E3 enzymes can be very substrate specific, leading to the specialized degradation of a small subset of proteins within the cell. E2 enzymes are the intersection between E1 and E3 enzymes and help to determine the ubiquitination of specific target proteins by interacting with different types of E3 enzymes.

    Figure \(\PageIndex{9}\) below shows an interactive iCn3D model of the Yeast proteasome in resting state (C1-a) (6J2X). (long load)

    Yeast proteasome in resting state (C1-a) (6J2X).png

    Figure \(\PageIndex{9}\): Yeast proteasome in resting state (C1-a) (6J2X). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/icn3d/share.html?1AmGmkghbZD2zute7

    It's too complex to discuss this in much detail. The chains are presented in different colors. You should able to find the alpha and beta chains of the core 20S particle. The regulatory cap proteins comprising the lid are on top of the alpha ring.

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    This page titled 27.3: Translational Regulation and Protein Degradation is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski and Patricia Flatt.

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