Protein breakdown in prokaryotic and eukaryotic cells is a continuous cycle that must be regulated. In the cytosol of most cells the S20 proteasome complex functions as the mediator of protein degradation, and possibly nucleic acids as well (6). The protein complex, via. several degradation pathways, serves to recycle the old proteins of all cells into smaller peptides that can be catabolized to form the building blocks of new proteins. Without this pool of digested protein to form enzymes, receptors, and intracellular structures (e.g. cytoskeleton), most cells would soon stop growing. The import of dietary amino acids could not keep up with the demand and cellular dysfunction would result because of waste protein build up. This shortage of amino acids for translation at the ribosome would affectedly slow the cells response to external stimuli
Degradation of proteins in the lysosome generate fragmented protein but most frequently degrade large (>300 Kd) proteins, and expel them rather than recycling them for anabolic actives such as t-RNA activation or protein synthesis. These vacuolarized proteins could not be acted upon by the peptidase in the cytosol to replenish free amino acids. The are expelled from the cell by exocytosis and lost. The proteasome is a midpoint in the protein degradation process because it generates peptide fragments less the ten amino acids in length that can be degrade by other peptidases into free amino acids.. The vesicular mean of proteolysis, such as the in the endoplasmic reticulum (ER), generate multiple fragment ratios, some of which may further degrade in the proteasome core enzyme (S20).
Translating messenger ribonucleic acid (mRNA) would also be affected due to lack of functional (activated) transfer RNA. The tRNAs do not function with out an AA group bound their 3’ end by aminoacyl-tRNA synthetase. This would nullify DNA’s control over cellular function and the cell would cease to be reactive to its environment..
The synthesis of ATP is dependent on enzymes (proteins made of AAs). Short peptides (antigens) are generated by the S20 proteasome’s digestion of large proteins, in both the nucleus and cytosol (4). Once hydrolyzed into smaller peptides that are broken down further, by other proteases, into AAs for translation, or processed for antigen presentation on the cells surface. Therefore, the proteasome is vital to the function of every living cell, because of the proteolytic properties it possesses as the intermediate in protein degradation. Thus, proteins can be directly degraded in the cytosol by the proteasome or the may first be vesicularly degraded and then expelled. Vesicular degradation causes the lose of amino acids to the extracelluar matrix, unlike proteasome degradation which recycles amino acids.
The proteasome can also induce cell apoptosis (mediated cell death) (17) when it is inactivated. A process speculated to involve phosporylation of the S11 cap. This causes slowing of the cells metabolic rate, due to lack of amino acids influx, until death occurs.
There are several other, immediate, means of apoptosis that involve phagocytosis by cytotoxic T-cells or protein pore assemble of the ‘membrane attack complex’. This attack complex is formed by interaction with antibodies (IgG and IgM) and the C1 protein complex bound to these immunoglobins. It cleaves and activates the proenzymes C3. The C3 enzyme embeds in the extracelluar membrane and facilitates the formation of the C5678 insertion protein of the ‘membrane attack complex’. Once inserted C5678 repeatedly polymerizes with the C9 protein to form a channel that breaches the lipid bilayer and allows the cytosol to leak out. The channel is formed by the termination of the C9 polymerization with the connection to the C56789999999… polymer. to close the loop at C5. The cylinder formed allows cytoplasm material to spill into the extracelluar space. The above mentioned systems are all extracelluar in nature.
Control over the S20 proteasome’s function must be maintained and adaptive to the changing needs of the cell and/or the organism. The proteasome is the primary non-vesicular means of protein catabolism in all eukaryotic cells and serves to regulate protein half-life in the cytosol and nucleus (5). Its role in cellular catabolism of protein (mRNA?) has expanded during evolution in eukaryotes. The advance functions that will be discussed include extracelluar mediation by the immune system systems (e.g. g-interferon)(29), as well as an intracellular mediator protein called the ‘ubiquitinating enzyme complex’ (UEC) (23,27).
The primary functional unit of this complex is the S20 proteasome, which contains 28 peptide subunits in two distinct types that join to form a circle with seven identical monomers per heptameric ring (i.e. a7 or b7). The heptameres (rings) are then stacked to form a cylinder in a 1. {a7} 2. {b7} 3. {b7} 4. {a7} tertiary structure[see Appendix A] (8,19). This conglomeration of multiple regulator subunits (S20 proteasome) is directly responsible for the nonvesicular breakdown of proteins into smaller peptide fragments less than 10 amino acids in length (10,17).
The abba cylinder is 15 nm long), the a rings and b rings serves to shield the 14 internal reaction sites from the external cytosolic environment. These 14 sites are on the interior surface of the cylinder 3.0 nm apart in two b rings of seven: 7a[7b7b]7a and prevents the majority of proteins that encounter the proteasome from being hydrolyzed (14). The proteasome safeguards the cell by allowing only certain proteins to enter through its oculus that is 3.0 nm diameter), as well as regulating the type and rate (Vmax) of AA breakdown (9,10). Regulation of protein entrance in to the oculus is still unknown, but the process could involve heat shock proteins (HSP) which are intermolecular chaperones that assist in unfolding and folding of proteins. Once unfolded by reduction of disulfide bonds, removal of prosthetic groups, and disruption of hydrogen bonding the streamlined peptide can enter passively or actively enter into the core of the complex.
The general structure of the S20 proteasome complex is conserved throughout all forms of life (11,18), however it has increased catalytic properties in higher eukaryotes. The complex can associate with other regulatory proteins in eukaryotes, such as S11 activator and S19 ATP-dependent degradation protein complex. These modules modify the proteolytic properties of the proteasome. Several regulatory subunits modify the function of the S20, S19, and S11 complexes.
The b subunit family may have diverged from a single gene for the a subunit early in its (their) evolution, and contain similarity in their AA sequences. Gene duplication occurred before the divergence of Archaebacter and eucaryotic organisms (21,30). After the divergence to eucaryotes, the b subunit mutated into several form a family of catalytic activators. The predominant two b subunit mutants were LMP2, and LMP7 (low molecular weight protein). They developed through a series of mutations on chromosome 6 (Homo sapiens: 6p22 region LMP2 and LMP7) and are now incorporated into the major histocompatibility complex (MHC 1; 6p22) gene region (11) of the immune system. A series of duplications in the primordial a subunit gene and subsequent mutation of the b subunits family caused the specialized function of eukaryotic proteasomes. These mutations created specialized subset of functional b subunits in the S20 proteasome structure. Modified b subunits (i.e. mutated a gene product) still incorporated into the heptameric (seven monomers per ring), and cylindrical core complex (stack in the abba configuration) of the S20 proteasome (12,28). The Acheobacter proteasome (673 Kd) (27) contains only homogeneous heptamers (seven identical monomers per ring) of a and b in the standard stacking abba structure. This primitive structure, or ur-proteasome, degrades small peptides. The antibody (MCA) marked amino acid sequence LLE (MCA-LL’E), was degrade by hydrolysis of glutamates [E] at the carboxyl terminus of leucine [L] in vitro (10,18). The complete sequence (AA) of archaebacterium Thermoplasma acidophilum’s S20 proteasome has been identified (21). The complex structure of this protein was determined by x-ray crystallography, and a molecular model may be accessed through the Internet by selecting 3D Structures with keyword: proteasome at the NCBI website (27).
Most research points to the fact the b subunits exhibit the catalytic properties of the S20 proteasome, and the a subunits are purely structural in nature (10,12,18,21). However, some evidence suggests that a subunits have catalytic properties as an RNAse. There were two a mutants discovered in eucaryotes. These mutant a subunits where designated Zeta (z) and Iota (i). Tobacco mosaic virus RNA was degraded in the presence of these subunits, and was otherwise left intact when treated with the remaining proteasome subunits. Experimentation suggested the a subunit Zeta (z) was more reactive (decreased Km) to the viral RNA (6). No additional direct evidence (primary sources) of RNAse activity was discovered. If the eucaryotic S20 proteasome possesses both RNAse and protease reaction sites in its catalytic core, it could be the primary regulator of protein formation (through mRNA degradation), and destruction (e.g. UEC/ubiquitin) in the cytosol.
The b subunit family contains many mutants, although only LMP2 and LMP7 are discussed here. These mutants of the primordial a subunit (gene) moved to a more advantageous gene region on chromosome 7 during the process of evolution. This region contains the MHC 1 protein that is responsible for antigen presentation on the cellular surface. Interferon is an external immune signals from T helper cells (20,22) that causes the MHC 1 gene region to be activated, and transcription (mRNA production) of the LMP2 and LMP7 subunits begins, as well as MHC 1.
MHC 1 is a protein produced in response to signaling by T helper cells and is responsible for binding the antigen produced by the proteolytic breakdown in the proteasomes core. The MHC 1 protein has a pocket formed by two a Helices. This pocket has a high affinity for nanopeptide with basic C-terminus R-groups such as arginine and lysine. Once bound to the HMC-1 the bound antigen is extruded to the cell surface for antigen presentation to the cytotoxic T cells. Cytotoxic T cells bind to the MHC 1 antigen complex via. a reciprocal docking protein on the its surface and CD8 adhesion protein.
On a cellular level, g interferon increases the rate of antigen presentation involving the MHC 1 / cytotoxic T-cell mechanism (18), because of the increased receptor production (MHC 1 protein) and the increased antigen production by the proteasome complex. (8,9,22)
The formation of the mature eukaryotic S20 proteasome (650 Kd) complex is a timed event in which several heptamers must come together and form a stacked cylinder. The incorporation of the b subunit within a heptamer ring is modified by the external affect of g-interferon. On the MHC 1 gene LMP2 is transcribed disproportionately to LMP7 (LMP2/LMP7>1.0), possibly due to the distance from the promoter region of the MHC 1 gene. This causes higher levels of LMP2 to bind in the b heptamers (heterogeneous LMP2/LMP7). Once incorporated these LMP2 subunits cause changes in the catalytic output of the S20 proteasome (9,10,18,27). Experimentation with g-interferon on human cells caused stimulation of the MHC 1 gene region (3), and subsequently produced altered b heptamers with high levels of LMP2. Purification (crystallization) and testing of proteasomes showed that the high levels of LMP2 cause increased peptide hydrolysis after basic residues in vitro, and reduce hydrolysis of acidic peptides. The LMP2 subunit is therefore promoting the pathway of the MHC 1 immune system response (via g-interferon stimulation). The majority of peptide hydrolysis occurs at the C-terminus of basic amino acids and they may be utilized as antigenic peptides that bind to the antigen presentation protein (MHC 1). (8,9,17,20,28). Alteration of the LMP7 (LMP2/LMP7 <1.0) ratios serves to promote the hydrolysis of basic and hydrophobic peptide, although not as drastically as LMP2. The role of LMP7 is thought to be that of housekeeping on a regular basis, until the promotion of LMP2 production by the immune system (18). The gene for the production of a/b subunits is not isolated to 6p22 in the human genome. There have been at least nine duplications of the primordial a subunit sequence (11).
The core S20 proteasome in therefore regulated by g-interferon from T helper cells stimulates hydrolysis at the C-terminus of basic R-Group peptides to form peptides 7-9 AA in length (10) for MHC 1 presentation to cytotoxic T cells (22). Once secreted g-interferon (IL) increases LMP2 gene transcription levels (mRNA) and may stimulate S11 gene transcription. This processes increased the breakdown of proteins into peptide fragments following a positively charged (basic C-terminus R-group) residues such as lysine and arginine. These digested peptide (9 AAs antigens) bind with the MHC 1 presentation protein at an increased rate. Once the antigen is bound the MHC 1 protein, they are extruded to the cell surface for recognition and destruction by Cytotoxtic T cells. This is the primary immune system function of the S20 proteasome.
The core protein has the ability to associate with other enzyme complex such as S11 and S19. These complexes confer additional proteolytic degradation mechanisms and/or increasing the overall rate of peptide hydrolysis. The most thoroughly studied component is the S11 activator. The Protein Activator S11 does not occur in lower eucaryotes such as Saccharomyces cerevisiae (16), but is found in higher eucaryotes. It docks with the S20 proteasome at one or both ends and reduces the oculus size to less than 3 nm (approximately 2.0 nm) (14,15,18). The S11 protein is also a heterogeneous heptamer made of PA28a and PA28b subunits, but may incorporate a similarly peptide termed the ‘Ki antigen’ or PA28g (16,30). Most evidence points to the symmetrical nature of the host protein . The S20 proteasome is 14.8 nm by 11.3 nm, with a 3.0 nm oculus at either end (8). The capping of the proteasome involves interaction with the a subunit heptamers of S20 and PA28 heptamer (PA28[abba]PA28) This activation by S11 restricts the openings, yet paradoxically increases the catalytic properties of the newly formed complex of S20 proteasome and S11 activator (S11 +S20 + S11; see Appendix A) (1).
Synthetic activators (homoheptamers PA28a, PA28b , PA28g, and a heteroheptamer of PA28a / PA28b) were tested to determine their affect on the catalytic nature of the activated proteasome in vitro (7,14). These heptameric activators bound to the proteasome and altered its catalytic properties. The increase in catalytic nature can not be attributed to a more confined reaction center, because variations exist in the experimental data (14,16). Succinyl-LLVY-7-animo-4-methylcoumarin was added to isolated human placenta PA28 protein, and increased breakdown was observed at equal moral ratios of a/b. Proteasomes samples (1 mg assay) with PA28b (0.5 mg) were test with increasing concentration of PA28a monomer (0.0-1.0 mg). This stimulated formation of heteroheptamers (PA28a / PA28bThe Vmax peaked at a 1:1 molar ration of PA28a / PA28b, and the activated S20 complex also showed a decrease in Km (16). It is therefore proposed that the PA28 is most functionally stable in the a/b heteroheptamer. Several reaction centers have been discovered on the PA28a subunit of the S11 activator. One such AA sequence, KEKE, serves to guide the docking of the S11 with the S20 proteasome. This motif contains alternating lysine (Lys) and glutamate (Glu) resides that possesses an alternating charge as well (K+E-K+E-) (16). It is reasonable that anti-KEKE motif exists on the proteasomes a subunit (helix) to facilitate docking, although none is mention in research. Some evidence suggests that the PA28 may be allosterically affect (deactivated) by phosphorylation of a serine (Ser) residue (16). No experimental evidence clarifies the reason for this deactivation (by phosphorylation of Ser), or if it is per-assemble or post-assemble in nature. Further research reveals that the alteration of PA28a / PA28b / Ki-Atigen ratios produce marked changes in the output of the activated proteasome complex (14). Fluorogenic peptides were added to proteasomes isolated from human RBCs and recombined heteroheptameric PA28 (a/b), and homohetromeric PA28 (a,b,g). The tagged MCA-AAs were added to (100 mM) proteasomes (PA28a,b,Ki,a/bin 6.7 pH) and the reaction was monitored using an emission spectrometer (at 335 nm). The breakdown of these peptides with different PA28 combinations showed that Ki-Atigen bound to the proteasome more readily than a or b, but it did not bind better than the heteroheptamer a/b (14). Further, more the subunits show distinct differences in the AA sequences they cleaved. The PA28a showed increased hydrolysis of (MCA-LLE) negatively charged residues (up to twenty times faster than the S20 proteasome). The PA28b heptamer showed increased breakdown of (MCA-LRR) positively charged residues, while the Ki-Antigen showed increased hydrolysis of (MCA-LLVY) hydrophobic residues (14). The hetroheptamer a/b showed the most increase in activation, and in the degradation of all three tagged AA sequences. Some experimental evidence states that g-interferon may also induce transcription of PA28 subunits (14,29).
The less known activator S19, is an ATP dependent proteolytic mechanism that serves to rid the cell of damaged or foreign proteins when it is docked with the S20 complex. The mean of association and placement of the S19 subunit is still under speculation. The most probable arrangement would be on the exterior of the S11 cap (S19/S11(abba)S11/S19) in a symmetrical fashion (see Appendix A). Protein half-life in the cytosol is controlled by several enzyme systems, but the S19 regulator complex performs most cytosolic enzyme mediated (UEC) proteolysis when joined to the S20 core complex. Proteins are detect by the UEC and a Lys residue near their N-terminus is covalently modified, by the attachment of ubiquitin (76 AA) (24,25). A secondary enzyme known as E2 (2,23) polymerizes ubiquitin at the primary ubiquitin’s N-termins to the C-terminus of another ubiquitin into long chains (28). The long chain formed by E2 is then bound to the S19 complex. First, the UEC tagged protein is polyubquitinated by E2, and then bound to the S19 complex on top of the S20 cylinder. The S19/ubiquitin binding site in unknown, but it might possibly be ubiquitin’s single external alpha helix. The S19 complex resembles a hinged lid that is tilted at a 45-degree angle. The lid consists of ring structure similar to the a/b heptamer of the proteasome. This ring structure has an opening approximately 10 nm in diameter and appears to be associating with the C-terminus of the ubiquitin molecule (the point of tagged protein attachment). It is postulated that hydrolysis of ATP by the S19 complex powers the depolymerization of the polyubiquitin chain to reel in the tagged protein (13,28). The UEC enzyme therefore functions to tag proteins for destruction by the proteasome (S19).
The UEC can detect the terminal amino acid sequence of proteins and functions as housekeeping enzyme. Although most peptides have a methionine N-terminus the second AA in the sequence is also important. In some cases, the N-terminus Met may be remove by methionine aminopepidases exposing the AA in position two. The UEC has a low affinity for amino acids such as: Met, Ser, Thr, Ala, Val, Cys, Gly, and Pro. In eucaryote there are three levels of destabilization of the protein structure with respects to UEC tagged degradation pathway. A primary destabilizing AA is Arg because it reduces protein half-live to less than three days. Secondary destabilizing amino acids are Asp and Glu. These secondary destabilizers are modified by the attachment of Arg to their side groups by arginyl-tRNA-proteintransferase (AtRNAP)(28). Tertiary destabalizers such as Asn, and Gln must first be converted to Asp and Glu to be modified by AtRNAP-transferase. These amino acids stabilize newly formed proteins. Enzymatic modifications of the target protein’s N-terminus cause a delay tin the degradation process allowing a longer half-life (24,25,26) and acetylation of the N-terminus during protein maturation may block UEC’s detection of such proteins (28).
The extent of cellular control over the degradation of protein in the cytosol has evolved from simplistic means in prokaryotic organisms (i.e. Thermoplasma acidophilum) to the complex cellular mediated S20 (with S11 and S19) proteolysis of higher eucaryotes (i.e. Homo sapiens). The proteasome may be allosterically regulated by phosphorylation of a Serine residue on the S11 cap. The UEC mechanism further adds to the proteasomes ability to digest foreign or damaged peptides. Once again, the most probable conformation of the complex and its constituents would be in a symmetrical arrangement with the S20 proteasome as the core protein, followed by the S11 activator, with the S19 docking on the outer rim of the S11 cap (S19[S11{S20}S11]S19). Further studies must been done in order to establish the role of these components in the human cellular protein and RNA degradation systems. Once these enzymes are understood, the intracellular means of AA catabolism may be elucidated.
Appendix A.
References:
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2. Cook WJ, Jeffrey LC, Carson M, Chen Z, Pickart CM Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2). J Biol Chem 1992 Aug 15;267(23):16467-16471
3. Koopmann JO, Hammerling GJ, Momburg F Generation, intracellular transport and loading of peptides associated with MHC class I molecules. Curr Opin Immunol 1997 Feb;9(1):80-88
4. Reits EAJ, Benham AM, Plougastel B, Neefjes J, Trowsdale J Dynamics of proteasome distribution in living cells. EMBO J 1997 Oct 15;16(20):6087-6094
5. Nederlof PM, Wang HR, Baumeister W Nuclear localization signals of human and Thermoplasma proteasomal alpha subunits are functional in vitro. Proc Natl Acad Sci U S A 1995 Dec 19;92(26):12060-12064
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8. Yang Y, Fruh K, Ahn K, Peterson PA In vivo assembly of the proteasomal complexes, implications for antigen processing. J Biol Chem 1995 Nov 17;270(46):27687-27694
9. Gaczynska M, Rock KL, Spies T, Goldberg AL Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc Natl Acad Sci U S A 1994 Sep 27;91(20):9213-9217
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12. Brown MG, Monaco JJ Biochemical purification of distinct proteasome subsets. Enzyme Protein 1993;47(4-6):343-353.
13. Loayza D, Michaelis S Role for the ubiquitin-proteasome system in the vacuolar degradation of Ste6p, the a-factor transporter in Saccharomyces cerevisiae. Mol Cell Biol 1998 Feb;18(2):779-789
14. Realini C, Jensen CC, Zhang Z, Johnston SC, Knowlton JR, Hill CP, Rechsteiner M Characterization of recombinant REGalpha, REGbeta, and REG gamma proteasome activators. J Biol Chem 1997 Oct 10;272(41):25483-25492
15. Johnston SC, Whitby FG, Realini C, Rechsteiner M, Hill CP The proteasome 11S regulator subunit REG alpha (PA28 alpha) is a heptamer. Protein Sci 1997 Nov;6(11):2469-2473
16. Kuehn L, Dahlmann B Structural and functional properties of proteasome activator PA28. Mol Biol Rep 1997 Mar;24(1-2):89-93
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18. Schmidt M, Kloetzel PM Biogenesis of eukaryotic 20S proteasomes: the complex maturation pathway ofa complex enzyme. FASEB J 1997 Dec;11(14):1235-1243
19. Gerards WL, Enzlin J, Haner M, Hendriks IL, Aebi U, Bloemendal H, Boelens W The human alpha-type proteasomal subunit HsC8 forms a double ring like structure, but does not assemble into proteasome-like particles with thebeta-type subunits HsDelta or HsBPROS26.J Biol Chem 1997 Apr 11;272(15):10080-10086
20. Gaczynska M, Rock KL, Goldberg AL Role of proteasomes in antigen presentation. Enzyme Protein 1993;47(4-6):354-369
21. Lowe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science 1995 Apr 28;268(5210):533-539
22. Marusina K, Monaco JJ Peptide transport in antigen presentation. Curr Opin Hematol 1996 Jan;3(1):19-26
23. Cook WJ, Jeffrey LC, Carson M, Chen Z, Pickart CM Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2). J Biol Chem 1992 Aug 15;267(23):16467-16471
24. Cook WJ, Martin PD, Edwards BF, Yamazaki RK, Chau V Crystal structure of a class I ubiquitin conjugating enzyme (Ubc7) from Saccharomyces cerevisiae at 2.9 angstroms resolution. Biochemistry 1997 Feb 18;36(7):1621-1627
25. Cook WJ, Jeffrey LC, Kasperek E, Pickart CM Structure of tetraubiquitin shows how multiubiquitin chains can be formed. J Mol Biol 1994 Feb 18;236(2):601-609
26. Cook WJ, Jeffrey LC, Xu Y, Chau V Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4. Biochemistry 1993 Dec 21;32(50):13809-13817
27. National Center for Biological Investigation (National Institute of Health) http://www.ncbi.nlm.nih.gov/Entrez/structure.html
28. Ahn JY, Tanahashi N, Akiyama K, Hisamatsu H, Noda C, Tanaka K, Chung CH, Albert, MHC- encoded ABC transporters transfer peptide fragments from the cytosol to ER lumen. The Cell. 3th Ed. (1997); 1236-1238
29. Shibmara N, Willy PJ, Mott JD Primary structures of two homologous subunits of PA28, a gamma-interferon-inducible protein activator of the 20S proteasome. FEBS Lett 1995 Jun 5;366(1):37-42
30. Kandil E, Kohda K, Ishibashi T, Tanaka K, Kasahara M PA28 subunits of the mouse proteasome: primary structures and chromosomal localization of the genes. Immunogenetics 1997;46(4):337-344
Copyright © 1998 by Michael Osgood and Koni Stone
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