Protein Synthesis, Processing, and Regulation

Protein Synthesis, Processing, and Regulation
9 Protein Synthesis, Processing, and Regulation

9 Protein Synthesis, Processing, and Regulation
Translation of mRNA Protein Folding and Processing Regulation of Protein Function Protein Degradation

Introduction Translation is the synthesis of proteins as directed by mRNA templates, the first step in the formation of functional proteins. Polypeptide chains must fold into appropriate conformations and often undergo various processing steps, sorting, and transport.

Introduction Gene expression is regulated at the level of translation in both prokaryotic and eukaryotic cells. There are also multiple controls on amount and activities of proteins, which ultimately regulate all aspects of cell behavior.

Translation of mRNA Proteins are synthesized from mRNA templates by a process that has been highly conserved throughout evolution. All mRNAs are read in the 5′ to 3′ direction, and polypeptide chains are synthesized from the amino to the carboxy terminus.

Each amino acid is specified by three bases (a codon) in the mRNA.
Translation of mRNA Each amino acid is specified by three bases (a codon) in the mRNA. Translation is carried out on ribosomes, with tRNAs serving as adaptors. Protein synthesis involves interactions between the three types of RNA (mRNA, tRNA, rRNA), plus other proteins.

Translation of mRNA tRNAs align amino acids with corresponding codons on the mRNA template. They are 70–80 nucleotides long and have characteristic cloverleaf structures resulting from base pairing between different regions.

Figure 9.1 Structure of tRNAs (Part 1)

Translation of mRNA All tRNAs fold into compact L shapes, to fit onto ribosomes during translation. They have the sequence CCA at the 3′ end, and amino acids are covalently attached to the ribose of the terminal adenosine. The anticodon loop binds to the appropriate codon by complementary base pairing.

Translation of mRNA Attachment of amino acids to specific tRNAs is mediated by enzymes called aminoacyl tRNA synthetases. Each of these 20 enzymes recognizes a single amino acid, as well as the correct tRNA to which it should attach.

Attachment occurs in two steps:
Translation of mRNA Attachment occurs in two steps: 1. The amino acid is joined to AMP, forming aminoacyl AMP. 2. The amino acid is transferred to the 3′ CCA end of the tRNA and AMP is released.

Figure 9.2 Attachment of amino acids to tRNAs

Most amino acids are specified by more than one codon.
Translation of mRNA The amino acid is then aligned on the mRNA template by complementary base pairing. Most amino acids are specified by more than one codon. Cells have about 40 different tRNAs for the 20 different amino acids.

This allows G to pair with U, and inosine (I) to pair with U, C, or A.
Translation of mRNA Some tRNAs can recognize more than one mRNA codon, as a result of nonstandard base pairing (wobble) at the third codon position. This allows G to pair with U, and inosine (I) to pair with U, C, or A. (Guanosine is modified to inosine in the anticodons of some tRNAs.)

Figure 9.3 Nonstandard codon–anticodon base pairing (Part 1)

Figure 9.3 Nonstandard codon–anticodon base pairing (Part 2)

Translation of mRNA Ribosomes are named according to their sedimentation rates in ultra- centrifugation: 70S for bacterial and 80S for eukaryotic. Cells have many ribosomes, illustrating the importance of protein synthesis. E. coli has about 20,000; growing mammalian cells can have 10 million.

All ribosomes have two subunits.
Translation of mRNA All ribosomes have two subunits. Each subunit contains rRNA and characteristic proteins. The subunits of eukaryotic ribosomes are larger and have more proteins than prokaryotic ribosomes.

Figure 9.4 Ribosome structure (Part 1)

Figure 9.4 Ribosome structure (Part 2)

Translation of mRNA Ribosomes can be formed in vitro by self-assembly from purified ribosomal proteins and rRNAs. This provides an important experimental tool, allowing analysis of the roles of individual proteins and rRNAs.

Subsequent folding results in distinct 3-D structures.
Translation of mRNA rRNAs form characteristic secondary structures by complementary base pairing. Subsequent folding results in distinct 3-D structures.

Figure 9.5 Structure of 16S rRNA

It was later shown that rRNA has catalytic activity.
Translation of mRNA It was first thought that rRNAs played only a structural role in ribosomes. It was later shown that rRNA has catalytic activity. Noller and colleagues in 1992 showed that the large ribosomal subunit can catalyze formation of peptide bonds even after 90% of ribosomal proteins have been removed.

Translation of mRNA In 2000, unambiguous evidence for rRNA catalysis came from high- resolution structural analysis of the 50S ribosomal subunit. Ribosomal proteins are absent from the site of the peptidyl transferase reaction, showing that rRNA is responsible for catalyzing peptide bond formation.

Figure 9.6 Structure of the 50S ribosomal subunit

Translation of mRNA It is now thought that ribosomal proteins play a largely structural role, and the large ribosomal subunit functions as a ribozyme. This has evolutionary implications: RNAs are thought to have been the first self- replicating macromolecules.

Translation of mRNA The role of rRNA in the formation of peptide bonds extends the catalytic activities of RNA beyond self- replication to direct involvement in protein synthesis. This may provide an important link for understanding the early evolution of cells.

mRNAs have noncoding untranslated regions (UTRs) at the ends.
Translation of mRNA mRNAs have noncoding untranslated regions (UTRs) at the ends. Most eukaryote mRNAs are mono- cistronic, encoding a single protein. Prokaryotic mRNAs are often polycistronic, encoding multiple proteins, each of which is translated from an independent start site.

Figure 9.7 Prokaryotic and eukaryotic mRNAs

Translation of mRNA In both prokaryotes and eukaryotes, translation always starts with methionine, usually encoded by AUG. The signals that identify initiation codons are different in prokaryotic and eukaryotic cells.

Translation of mRNA Initiation codons in bacterial mRNAs are preceded by a Shine-Dalgarno sequence, that aligns the mRNA on the ribosome. They can initiate translation at the 5′ end of an mRNA and at internal initiation sites of polycistronic mRNAs.

Translation of mRNA Eukaryotic mRNAs are recognized by the 7-methylguanosine cap at the 5′ end. The ribosomes then scan downstream of this cap until they encounter the initiation codon.

Figure 9.8 Signals for translation initiation

The large ribosomal unit then joins, forming a functional ribosome.
Translation of mRNA Translation occurs in three stages: initiation, elongation, and termination. A specific initiator, methionyl tRNA, and the mRNA bind to the small ribosomal subunit. The large ribosomal unit then joins, forming a functional ribosome.

Figure 9.9 Overview of translation

Translation of mRNA Many nonribosomal proteins are also required for various stages of translation.

Table 9.1 Translation Factors

Translation of mRNA In bacteria, initiation starts with a 30S ribosomal subunit bound to initiation factors IF1 and IF3. Then the mRNA, initiator N-formylmethionyl (fMet) tRNA, and IF2 (bound to GTP) join the complex. IF1 and IF3 are released, a 50S subunit binds to the complex, and IF2 is released.

Figure 9.10 Initiation of translation in bacteria

Translation of mRNA In eukaryotes initiation is more complex, and requires at least 12 proteins, designated eIFs (eukaryotic initiation factors).

Figure 9.11 Initiation of translation in eukaryotic cells (Part 1)

Figure 9.11 Initiation of translation in eukaryotic cells (Part 2)

Translation of mRNA Some viral and cellular eukaryotic mRNAs have internal ribosome entry sites (IRESs) at which translation can initiate independently of the 5′ cap. For viral mRNAs, IRES sequences bind directly to eIF4G complexed to eIF4A, or to 40S ribosomal subunits.

Figure 9.12 Initiation of translation at internal ribosome entry sites

The initiator methionyl tRNA binds to the P site.
Translation of mRNA The mechanism of elongation in prokaryotic and eukaryotic cells is similar. Ribosomes have three binding sites: P (peptidyl), A (aminoacyl), and E (exit) sites. The initiator methionyl tRNA binds to the P site.

Translation of mRNA The next aminoacyl tRNA binds to the A site by pairing with the second codon of the mRNA. An elongation factor (EF-Tu in prokaryotes, eEF1α in eukaryotes) complexed to GTP brings the aminoacyl tRNA to the ribosome.

Figure 9.13 Elongation stage of translation (Part 1)

Translation of mRNA Selection of the correct aminoacyl tRNA determines the accuracy of protein synthesis. Base pairing alone can’t account for the accuracy of protein synthesis. A “decoding center” in the small ribosomal subunit recognizes correct codon-anticodon base pairs and discriminates against mismatches.

The initiator tRNA (uncharged) is now at the P site.
Translation of mRNA Insertion of the correct aminoacyl tRNA at A triggers a conformational change that induces hydrolysis of GTP/eEF1α and release of the elongation factor. The peptide bond is then formed, catalyzed by the large ribosomal subunit. The initiator tRNA (uncharged) is now at the P site.

Translation of mRNA Translocation: the ribosome then moves three nucleotides along the mRNA, positioning the next codon in the A site. This step translocates the peptidyl tRNA from A to P, and the uncharged tRNA from P to E.

Translation of mRNA A new aminoacyl tRNA binds to the A site and induces release of the uncharged tRNA from the E site. Translocation requires another elongation factor (EF-G in prokaryotes, eEF2 in eukaryotes) and is coupled to GTP hydrolysis.

Translation of mRNA As elongation continues, the eEF1α (or EF-Tu) released from the ribosome bound to GDP must be reconverted to its GTP form. This requires another elongation factor, eEF1βγ (EF-Ts in prokaryotes). Regulation of eEF1α by GTP binding and hydrolysis is a common method of protein regulation.

Figure 9.14 Regeneration of eEF1a/GTP

In eukaryotic cells eRF1 recognizes all three stop codons.
Translation of mRNA Elongation continues until a stop codon (UAA, UAG, or UGA) is translocated into the A site. Release factors recognize these signals and terminate protein synthesis. In prokaryotic cells RF1 recognizes UAA or UAG, RF2 recognizes UAA or UGA. In eukaryotic cells eRF1 recognizes all three stop codons.

Figure 9.15 Termination of translation (Part 1)

mRNAs can be translated simultaneously by several ribosomes.
Translation of mRNA mRNAs can be translated simultaneously by several ribosomes. Once a ribosome has moved away from the initiation site, another can bind to the mRNA and begin synthesis. A group of ribosomes bound to an mRNA molecule is called a polyribosome, or polysome.

Figure 9.16 Polysomes (Part 1)

Figure 9.16 Polysomes (Part 2)

Regulation of translation plays a key role in gene expression.
Translation of mRNA Regulation of translation plays a key role in gene expression. Regulation includes translational repressor proteins and noncoding microRNAs. Global translational activity is modulated in response to stress, nutrient availability, and growth factor stimulation.

Translation of mRNA Regulation of ferritin translation (a protein that stores iron) by repressor proteins: When iron is absent, iron regulatory protein (IRP) binds to a the iron response element (IRE) in the 5′ UTR, blocking translation.

Figure 9.17 Translational regulation of ferritin

Translation of mRNA Some translational repressors bind to specific sequences in the 3′ UTR. Some bind to initiation factor eIF4E, interfering with its interaction with eIF4G and inhibiting initiation of translation.

Figure 9.18 Translational repressor binding to 3' untranslated sequences

Translation of mRNA Proteins that bind to 3′ UTRs are also responsible for localizing mRNAs to specific regions of cells. Localization to specific regions of eggs or embryos is important in development, allowing proteins to be synthesized at appropriate sites.

Figure 9.19 Localization of mRNA in Xenopus oocytes

Translational regulation is very important during early development.
Translation of mRNA Translational regulation is very important during early development. Many mRNAs with short poly-A tails are stored in oocytes; translation is activated at fertilization or later stages. Lengthening the poly-A tails allows binding of poly-A binding protein (PABP), which stimulates translation.

In cells, it is an important mechanism of translational regulation.
Translation of mRNA RNA interference (RNAi), mediated by short double-stranded RNAs, is used as an experimental tool to block gene expression at the level of translation. In cells, it is an important mechanism of translational regulation.

RNA interference is mediated by:
Translation of mRNA RNA interference is mediated by: Small interfering RNAs (siRNAs)— produced from double-stranded RNAs by the nuclease Dicer. MicroRNAs (miRNAs)—transcribed by RNA polymerase II, then cleaved by nucleases Drosha and Dicer.

Translation of mRNA One strand of miRNA or siRNA is incorporated into an RNA-induced silencing complex (RISC). siRNAs generally pair with their targets and induce cleavage of the mRNA.

Figure 4.38 RNA interference

Figure 6.8 miRNAs (Part 1)

Figure 6.8 miRNAs (Part 2)

Most miRNAs form mismatches in the 3′ UTRs that repress translation.
Translation of mRNA Most miRNAs form mismatches in the 3′ UTRs that repress translation. The miRNA/RISC complex represses translation and targets the mRNA for degradation by stimulating deadenylation. 80

Figure 9.20 Regulation of translation by miRNAs

Up to one-half of protein-coding genes may be regulated by miRNAs.
Translation of mRNA As many as 1000 miRNAs are encoded in mammals; each can target up to 100 different mRNAs. Up to one-half of protein-coding genes may be regulated by miRNAs. They are important in embryonic development, and may play a role to cancer and other diseases.

Translation of mRNA Translation can also be regulated by modification of initiation factors. This results in global effects on overall translational activity rather than translation of specific mRNAs.

Translation of mRNA Phosphorylation of eIF2 and eIF2B by regulatory protein kinases blocks the exchange of bound GDP for GTP, inhibiting initiation of translation.

Figure 9.21 Regulation of translation by phosphorylation of eIF2 and eIF2B (Part 1)

Figure 9.21 Regulation of translation by phosphorylation of eIF2 and eIF2B (Part 2)

Translation of mRNA Regulation of eIF4E: Growth factors activate protein kinases that phosphorylate regulatory proteins (eIF4E binding proteins, or 4E-BPs). In the absence of growth factors, the nonphosphorylated 4E-BPs bind to eIF4E and inhibit translation.

Figure 9.22 Regulation of eIF4E

Protein Folding and Processing
Polypeptide chains must undergo folding and other modifications to become functional proteins. 3-D protein conformation results from interactions between the side chains of amino acids. All information for the correct conformation is provided by the amino acid sequence.

Chaperones are proteins that facilitate folding of other proteins. They act as catalysts that assist the self- assembly process without becoming part of the folded protein. They bind to and stabilize unfolded or partially folded polypeptides.

Chaperones bind to polypeptide chains that are still being translated on ribosomes. The chain must be protected from aberrant folding or aggregation with other proteins until synthesis of an entire domain is complete.

Figure 9.23 Action of chaperones during translation

Chaperones also stabilize unfolded polypeptide chains during transport into organelles. Example: Partially unfolded proteins stabilized by chaperones are transported across the mitochondrial membrane. Chaperones in the mitochondrion then facilitate folding.

Figure 9.24 Action of chaperones during protein transport

Many chaperones were initially identified as heat-shock proteins (Hsp), expressed in cells subjected to high temperatures. Hsp stabilize and facilitate refolding of proteins that have been partially denatured.

Hsp70 chaperones and chaperonins are found in both prokaryotic and eukaryotic cells. Hsp70 proteins stabilize polypeptide chains during translation and transport by binding to short hydrophobic segments.

The polypeptide is then transferred to a chaperonin, where folding takes place. Chaperonins consist of subunits arranged in two stacked rings to form a double-chambered structure. This isolates the protein from the cytosol and other unfolded proteins.

Figure 9.25 Sequential actions of chaperones

Defects in protein folding are responsible for protein misfolding diseases. Cystic fibrosis is caused by a mutation that results in one amino acid deletion that leads to improper folding of protein CFTR. CFTR transports Cl‒ ions across epithelial cell membranes.

Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes are associated with aggregation of misfolded proteins. The misfolded proteins form fibrous aggregates called amyloids, characterized by β-sheet structures.

Figure 9.26 Protein aggregation and amyloid formation (Part 1)

Figure 9.26 Protein aggregation and amyloid formation (Part 2)

Table 9.2 Representative Diseases Associated with Protein Aggregation

Alzheimer’s disease is characterized by two aggregate types in brain tissue: Neurofibrillary tangles (misfolded tau proteins) Amyloid plaques (aggregates of misfolded amyloid-β protein [Aβ]) 104

Molecular Medicine, Ch. 9, p. 342

Prions are misfolded proteins that can self-replicate. Diseases caused by prions include scrapie in sheep, mad cow disease, Creutzfeldt-Jakob disease, and kuru.

Infection by prions is based on amyloid formation of the protein PrP. In mammalian cells the normal α-helical form is PrPC. In the infectious form, PrP forms a misfolded amyloid structure, PrPSc. 107

PrPSc can propagate by inducing misfolding of PrPC proteins to the amyloid state. PrPSc can “replicate” by inducing autocatalytic amyloid formation of endogenous PrPC—a novel form of propagation that does not require any nucleic acid. 108

Figure 9.27 Prion propagation

Two enzymes act as chaperones by catalyzing protein folding: Protein disulfide isomerase (PDI) catalyzes disulfide bond formation. PDI is abundant in the ER, where an oxidizing environment allows (S—S) linkages. 110

Figure 9.28 The action of protein disulfide isomerase

Peptidyl prolyl isomerase catalyzes isomerization of peptide bonds that involve proline residues. Isomerization between the cis and trans configurations of prolyl-peptide bonds could otherwise be a rate-limiting step in protein folding.

Figure 9.29 The action of peptidyl prolyl isomerase

Proteolysis: cleavage of a polypeptide chain removes portions such as the initiator methionine from the amino terminus. Many proteins have amino-terminal signal sequences that target the protein for transport to a specific destination.

The signal sequence is inserted into a membrane channel as it emerges from the ribosome and the polypeptide chain passes through as translation proceeds. The signal sequence is then cleaved by a membrane protease (signal peptidase).

Figure 9.30 The role of signal sequences in membrane translocation

Proteolytic processing includes formation of active enzymes or hormones by cleavage of larger precursors. Example: Insulin is synthesized as a precursor polypeptide that goes through two cleavages to produce the mature insulin.

Figure 9.31 Proteolytic processing of insulin

In replication of HIV, a virus-encoded protease cleaves precursor polypeptides to form the viral structural proteins. The HIV protease is an important target in drug development for treating AIDS (in addition to reverse transcriptase) .

Glycosylation adds carbohydrate chains to proteins to form glycoproteins. The carbohydrate moieties play important roles in protein folding in the ER, in targeting proteins for transport, and as recognition sites in cell-cell interactions.

N-linked glycoproteins: the carbohydrate is attached to the nitrogen atom in the side chain of asparagine. O-linked glycoproteins: the carbohydrate is attached to the oxygen atom in the side chain of serine or threonine.

Figure 9.32 Linkage of carbohydrate side chains to glycoproteins

Glycosylation starts in the ER before translation is complete. An oligosaccharide is assembled on a lipid carrier (dolichol phosphate) in the ER membrane, then transferred to an asparagine residue. Further modifications result in many different N-linked oligosaccharides.

Figure 9.33 Synthesis of N-linked glycoproteins

O-linked oligosaccharides are added within the Golgi apparatus. They are formed by addition of one sugar at a time. Many cytoplasmic and nuclear proteins, including transcription factors, are also modified by addition of one O-linked N- acetylglucosamine residue.

Figure 9.34 Examples of O-linked oligosaccharides

Some eukaryotic proteins are modified with lipids, which often serve to anchor them to the plasma membrane.

Four types of lipid additions: 1. N-myristoylation: myristic acid (a fatty acid) is attached to an N-terminal glycine. These proteins are associated with the inner face of the plasma membrane.

Figure 9.35 Addition of a fatty acid by N-myristoylation

2. Prenylation: prenyl groups are attached to sulfur in the side chains of cysteine near the C terminus. Many of these proteins are involved in control of cell growth and differentiation, including the Ras oncogene proteins, responsible for many human cancers.

Figure 9.36 Prenylation of a C-terminal cysteine residue

3. Palmitoylation: palmitic acid (a fatty acid) is added to sulfur in the side chains of internal cysteine residues. This is also important in association of some proteins with the cytosolic face of the plasma membrane.

Figure 9.37 Palmitoylation

4. Glycolipids (lipids linked to oligosaccharides) are added to C- terminal carboxyl groups. They anchor the proteins to the external plasma membrane. The glycolipids have phosphatidylinositol: glycosylphosphatidylinositol (GPI) anchors.

Figure 9.38 Structure of a GPI anchor

Regulation of Protein Function
Cells can regulate the amounts and the activities of their proteins. Three mechanisms: Regulation by small molecules Phosphorylation and other modifications Protein-protein interactions

Regulation by small molecules Most enzymes are controlled by changes in conformation, often as a result of binding small molecules. This type of regulation is common in controlling metabolic pathways by feedback inhibition.

Feedback inhibition is an example of allosteric regulation: A regulatory molecule binds to an enzyme site that is distinct from the catalytic site.

Figure 9.39 Feedback inhibition

Many cellular proteins are regulated by GTP or GDP binding, including the Ras oncogene proteins. X-ray crystallography has revealed subtle conformational differences between the inactive GDP-bound and active GTP-bound forms.

Figure 9.40 Conformational differences between active and inactive Ras proteins

The small difference in protein conformation determines whether Ras can interact with its target molecule, which signals the cell to divide. Mutations in ras genes contribute to 25% of human cancers. Ras proteins are altered to be locked in the active GTP- bound conformation and continually signal cell division.

Phosphorylation and other modifications Phosphorylation is reversible; it can activate or inhibit proteins in response to environmental signals. Protein kinases transfer phosphate groups from ATP to the hydroxyl groups of side chains of serine, threonine, or tyrosine.

Phosphorylation is reversed by protein phosphatases, which catalyze hydrolysis of phosphorylated amino acids.

Figure 9.41 Protein kinases and phosphatases

Protein kinases are often components of signal transduction pathways. Sequential action of a series of protein kinases can transmit a signal from the cell surface to target proteins in the cell, resulting in changes in cell behavior in response to environmental stimuli.

Example: In muscle cells, epinephrine signals the breakdown of glycogen to glucose-1-phosphate, providing energy for increased muscular activity. This is catalyzed by glycogen phosphorylase, which is regulated by a protein kinase.

Figure 9.42 Regulation of glycogen breakdown by protein phosphorylation

The signaling pathway is initiated by allosteric regulation—epinephrine binds to a cell surface receptor, and cAMP binds to cAMP-dependent kinase. The signal is then transmitted to its target by the sequential action of protein kinases.

Aberrations in signaling pathways, especially in protein-tyrosine kinases, are responsible for some cancers. The first protein-tyrosine kinase was discovered in 1980 in studies of Rous sarcoma virus. Small molecule inhibitors of these enzymes are promising drugs for cancer treatment.

Key Experiment, Ch. 9, p. 353 (Part 3)

Other covalent modifications include: Acetylation of lysine Methylation of lysine and arginine Nitrosylation (addition of NO groups) to cysteine Glycosylation of serine and threonine

Figure 9.43 Modification of proteins by small molecules (Part 1)

Some proteins are regulated by covalent attachment of polypeptides. Addition of ubiquitin and other ubiquitin- like proteins, such as SUMO, affect a variety of functions. Addition of ubiquitin (ubiquitylation) is a multistep process.

Figure 9.44 Modification of proteins by ubiquitin

Histone modification by ubiquitin and SUMO is one mechanism for regulating transcriptional activity of chromatin. Ubiquitylation is also important in regulation of protein kinases, proteins involved in DNA repair, and in the control of endocytosis and vesicle trafficking. 159

Many of the proteins modified by SUMO are transcription factors and other nuclear proteins, whose localization is affected by sumoylation. 160

A protein modified by SUMO is Ran GTPase-activating protein (Ran GAP).
Protein Degradation A protein modified by SUMO is Ran GTPase-activating protein (Ran GAP). Ran GAP is associated with nuclear pore complexes and is required for import of proteins. Addition of SUMO to Ran GAP is thus necessary for all protein traffic between the cytoplasm and nucleus.

Protein-protein interactions Many proteins consist of multiple subunits; interactions between them can regulate protein activity. Example: cAMP-dependent protein kinase has two regulatory and two catalytic subunits in the inactive form. 162

cAMP binds to the regulatory subunits, which induces conformational change and dissociation of the complex. The free catalytic subunits are then enzymatically active protein kinases. cAMP acts as an allosteric regulator by altering protein-protein interactions.

Figure 9.45 Regulation of cAMP-dependent protein kinase

Protein Degradation Protein levels in cells are determined by rates of synthesis and rates of degradation. Half-lives of proteins vary greatly; differential rates of degradation are important in cell regulation.

Faulty or damaged proteins are recognized and rapidly degraded.
Protein Degradation Many regulatory proteins have short half lives; this allows levels to change quickly in response to external stimuli. Faulty or damaged proteins are recognized and rapidly degraded.

Ubiquitin is highly conserved in all eukaryotes.
Protein Degradation The major pathway of protein degradation in eukaryotes is the ubiquitin-proteasome pathway. Ubiquitin is highly conserved in all eukaryotes.

Protein Degradation Ubiquitin is attached to the amino group of the side chain of a lysine residue, then more are added to form a chain. Polyubiquinated proteins are recognized and degraded by a large protease complex, the proteasome.

Figure 9.46 The ubiquitin-proteasome pathway

Protein Degradation Many proteins that control fundamental cellular processes are targets for regulated ubiquitylation and proteolysis. Example: Cyclins that regulate progression through the division cycle of eukaryotic cells.

The active cyclin B–Cdk1 complex induces entry into mitosis.
Protein Degradation Entry of cells into mitosis is controlled in part by cyclin B, a regulatory subunit of Cdk1 protein kinase. The active cyclin B–Cdk1 complex induces entry into mitosis. Degradation of cyclin B by the proteasome then leads to inactivation of the Cdk1 kinase, allowing the cell to exit mitosis and return to interphase. 171

Figure 9.47 Cyclin degradation during the cell cycle

Protein Degradation Protein degradation can also take place in lysosomes—membrane-enclosed organelles that contain digestive enzymes, including proteases. Lysosomes digest extracellular proteins taken up by endocytosis, and take part in turnover of organelles and proteins.

Protein Degradation Containment of digestive enzymes in lysosomes prevents uncontrolled degradation of cell contents. Proteins move into lysosomes by autophagy: vesicles (autophagosomes) enclose small areas of cytoplasm or organelles and then fuse with lysosomes.

Figure Autophagy

Protein Degradation Autophagy is activated in nutrient starvation, allowing cells to degrade nonessential proteins and organelles and reutilize the components. Autophagy also plays a role in many developmental processes, such as insect metamorphosis, which involve extensive tissue remodeling.

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