Morpheeins are proteins that can form two or more different homo-oligomers (morpheein forms), but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit dictates which oligomer is formed.[1][2] Each oligomer has a finite number of subunits (stoichiometry). Morpheeins can interconvert between forms under physiological conditions and can exist as an equilibrium of different oligomers. These oligomers are physiologically relevant and are not misfolded protein; this distinguishes morpheeins from prions and amyloid. The different oligomers have distinct functionality. Interconversion of morpheein forms can be a structural basis for allosteric regulation, an idea noted many years ago,[3][4] and later revived.[1][2][5][6] A mutation that shifts the normal equilibrium of morpheein forms can serve as the basis for a conformational disease.[7] Features of morpheeins can be exploited for drug discovery.[1][5][8] The dice image (Fig 1) represents a morpheein equilibrium containing two different monomeric shapes that dictate assembly to a tetramer or a pentamer. The one protein that is established to function as a morpheein is porphobilinogen synthase,[2][9][10] though there are suggestions throughout the literature that other proteins may function as morpheeins (for more information see "Table of Putative Morpheeins" below).
Implications for drug discovery
Conformational differences between subunits of different oligomers and related functional differences of a morpheein provide a starting point for drug discovery. Protein function is dependent on the oligomeric form; therefore, the protein's function can be regulated by shifting the equilibrium of forms. A small molecule compound can shift the equilibrium either by blocking or favoring formation of one of the oligomers. The equilibrium can be shifted using a small molecule that has a preferential binding affinity for only one of the alternate morpheein forms. An inhibitor of porphobilinogen synthase with this mechanism of action has been documented.[5]
Implications for allosteric regulation
The morpheein model of allosteric regulation has similarities to and differences from other models.[1][6][11] The concerted model (the Monod, Wyman and Changeux (MWC) model) of allosteric regulation requires all subunits to be in the same conformation or state within an oligomer like the morpheein model.[12][13] However, neither this model nor the sequential model (Koshland, Nemethy, and Filmer model) takes into account that the protein may dissociate to interconvert between oligomers.[12][13][14][15] Nonetheless, shortly after these theories were described, two groups of workers[3][4] proposed what is now called the morpheein model and showed that it accounted for the regulatory behavior of glutamate dehydrogenase.[16] Kurganov and Friedrich discussed models of this kind extensively in their books.[17][18]
Implications for teaching about protein structure-function relationships
It is generally taught [citation needed] that a given amino acid sequence will have only one physiologically relevant (native) quaternary structure; morpheeins challenge this concept. The morpheein model does not require gross changes in the basic protein fold.[1] The conformational differences that accompany conversion between oligomers may be similar to the protein motions necessary for function of some proteins.[19] The morpheein model highlights the importance of conformational flexibility for protein functionality and offers a potential explanation for proteins showing non-Michaelis-Menten kinetics, hysteresis, and/or protein concentration dependent specific activity.[11]
Implications for understanding the structural basis for disease
The term "conformational disease" generally encompasses mutations that result in misfolded proteins that aggregate, such as Alzheimer's and Creutzfeldt–Jakob diseases.[20] In light of the discovery of morpheeins, however, this definition could be expanded to include mutations that shift an equilibrium of alternate oligomeric forms of a protein. An example of such a conformational disease is ALAD porphyria, which results from a mutation of porphobilinogen synthase that causes a shift in its morpheein equilibrium.[7]
Table of proteins whose published behavior is consistent with that of a morpheein
Substrate binding/turnover impacts multimerization,[23] Protein concentration dependent specific activity,[24] Different assemblies have different activities,[24] Conformationally distinct oligomeric forms.[23][24]
Effector molecules impact multimerization,[45] Mutations shift the equilibrium of oligomers,[46] Different assemblies have different activities,[45] disease-causing mutations at sites distant from active site[47]
Multiple/protein moonlighting functions,[50] Different assemblies have different activities,[50] pH-dependent oligomeric equilibrium,[50] Conformationally distinct oligomeric forms[51][52][53]
Effector molecules impact multimerization,[89] Multiple/protein moonlighting functions,[89] Different assemblies have different activities,[89] pH-dependent oligomeric equilibrium[89]
Multiple/protein moonlighting functions,[113] Substrate binding/turnover impacts multimerization,[114] Different assemblies have different activities,[115] Kinetic hysteresis[114]
Effector molecules impact multimerization,[137] Characterized equilibrium of oligomers,[135][136] Different assemblies have different activities[135][136][137]
Effector molecules impact multimerization,[152] Substrate binding/turnover impacts multimerization,[152] Different assemblies have different activities[152]
References
^ abcdeJaffe, Eileen K. (2005). "Morpheeins – a new structural paradigm for allosteric regulation". Trends in Biochemical Sciences. 30 (9): 490–7. doi:10.1016/j.tibs.2005.07.003. PMID16023348.
^ abcBreinig, Sabine; Kervinen, Jukka; Stith, Linda; Wasson, Andrew S; Fairman, Robert; Wlodawer, Alexander; Zdanov, Alexander; Jaffe, Eileen K (2003). "Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase". Nature Structural Biology. 10 (9): 757–63. doi:10.1038/nsb963. PMID12897770. S2CID24188785.
^ abNichol, L W; Jackson, W J H; Winzor, D J (1967). "A theoretical study of the binding of small molecules to a polymerizing protein system: a model for allosteric effects". Biochemistry. 6 (8): 2449–2456. doi:10.1021/bi00860a022. PMID6049469.
^Koshland, D. E.; Nemethy, G.; Filmer, D. (1966). "Comparison of Experimental Binding Data and Theoretical Models in Proteins Containing Subunits". Biochemistry. 5 (1): 365–85. doi:10.1021/bi00865a047. PMID5938952.
^Kurganov, B I (1982). Allosteric Enzymes: Kinetic Behaviour. Chichester: Wiley–Interscience. pp. 151–248. ISBN978-0471101956.
^Friedrich, P (1984). Supramolecular Enzyme Organization: Quaternary Structure and Beyond. Oxford: Pergamon Press. pp. 66–71. ISBN0-08-026376-3.
^Gerstein, Mark; Echols, Nathaniel (2004). "Exploring the range of protein flexibility, from a structural proteomics perspective". Current Opinion in Chemical Biology. 8 (1): 14–9. doi:10.1016/j.cbpa.2003.12.006. PMID15036151.
^ abcWeissmann, Bernard; Wang, Ching-Te (1971). "Association-dissociation and abnormal kinetics of bovine .alpha.-acetylgalactosaminidase". Biochemistry. 10 (6): 1067–72. doi:10.1021/bi00782a021. PMID5550813.
^ abcWeissmann, Bernard; Hinrichsen, Dorotea F. (1969). "Mammalian α-acetylgalactosaminidase. Occurrence, partial purification, and action on linkages in submaxillary mucins". Biochemistry. 8 (5): 2034–43. doi:10.1021/bi00833a038. PMID5785223.
^De Zoysa Ariyananda, Lushanti; Colman, Roberta F. (2008). "Evaluation of Types of Interactions in Subunit Association in Bacillus subtilis Adenylosuccinate Lyase". Biochemistry. 47 (9): 2923–34. doi:10.1021/bi701400c. PMID18237141.
^ abcPalenchar, Jennifer Brosius; Colman, Roberta F. (2003). "Characterization of a Mutant Bacillus subtilis Adenylosuccinate Lyase Equivalent to a Mutant Enzyme Found in Human Adenylosuccinate Lyase Deficiency: Asparagine 276 Plays an Important Structural Role". Biochemistry. 42 (7): 1831–41. doi:10.1021/bi020640+. PMID12590570.
^Hohn, Thomas M.; Plattner, Ronald D. (1989). "Purification and characterization of the sesquiterpene cyclase aristolochene synthase from Penicillium roqueforti". Archives of Biochemistry and Biophysics. 272 (1): 137–43. doi:10.1016/0003-9861(89)90204-X. PMID2544140.
^Jerebzoff-Quintin, Simonne; Jerebzoff, Stephan (1985). "L-Asparaginase activity in Leptosphaeria michotii. Isolation and properties of two forms of the enzyme". Physiologia Plantarum. 64: 74–80. doi:10.1111/j.1399-3054.1985.tb01215.x.
^ abEisenstein, Edward; Beckett, Dorothy (1999). "Dimerization of theEscherichiacoliBiotin Repressor: Corepressor Function in Protein Assembly". Biochemistry. 38 (40): 13077–84. doi:10.1021/bi991241q. PMID10529178.
^Streaker, Emily D.; Beckett, Dorothy (1998). "Coupling of Site-Specific DNA Binding to Protein Dimerization in Assembly of the Biotin Repressor−Biotin Operator Complex". Biochemistry. 37 (9): 3210–9. doi:10.1021/bi9715019. PMID9485476.
^ abcdeTong, E. K.; Duckworth, Harry W. (1975). "Quaternary structure of citrate synthase from Escherichia coli K 12". Biochemistry. 14 (2): 235–41. doi:10.1021/bi00673a007. PMID1091285.
^Bewley, Carole A.; Gustafson, Kirk R.; Boyd, Michael R.; Covell, David G.; Bax, Ad; Clore, G. Marius; Gronenborn, Angela M. (1998). "Solution structure of cyanovirin-N, a potent HIV-inactivating protein". Nature Structural Biology. 5 (7): 571–8. doi:10.1038/828. PMID9665171. S2CID11367037.
^Yang, Fan; Bewley, Carole A; Louis, John M; Gustafson, Kirk R; Boyd, Michael R; Gronenborn, Angela M; Clore, G.Marius; Wlodawer, Alexander (1999). "Crystal structure of cyanovirin-N, a potent HIV-inactivating protein, shows unexpected domain swapping". Journal of Molecular Biology. 288 (3): 403–12. doi:10.1006/jmbi.1999.2693. PMID10329150. S2CID308708.
^ abBarrientos, LG; Gronenborn, AM (2005). "The highly specific carbohydrate-binding protein cyanovirin-N: Structure, anti-HIV/Ebola activity and possibilities for therapy". Mini Reviews in Medicinal Chemistry. 5 (1): 21–31. doi:10.2174/1389557053402783. PMID15638789.
^ abcRochet, Jean-Christophe; Brownie, Edward R.; Oikawa, Kim; Hicks, Leslie D.; Fraser, Marie E.; James, Michael N. G.; Kay, Cyril M.; Bridger, William A.; et al. (2000). "Pig Heart CoA Transferase Exists as Two Oligomeric Forms Separated by a Large Kinetic Barrier". Biochemistry. 39 (37): 11291–302. doi:10.1021/bi0003184. PMID10985774.
^Frank, Nina; Kery, Vladimir; MacLean, Kenneth N.; Kraus, Jan P. (2006). "Solvent-Accessible Cysteines in Human Cystathionine β-Synthase: Crucial Role of Cysteine 431 inS-Adenosyl-l-methionine Binding". Biochemistry. 45 (36): 11021–9. doi:10.1021/bi060737m. PMID16953589.
^Kery, Vladimir; Poneleit, Loelle; Kraus, Jan P. (1998). "Trypsin Cleavage of Human Cystathionine β-Synthase into an Evolutionarily Conserved Active Core: Structural and Functional Consequences". Archives of Biochemistry and Biophysics. 355 (2): 222–32. doi:10.1006/abbi.1998.0723. PMID9675031.
^ abcdStewart, L C; Klinman, J P (1988). "Dopamine Beta-Hydroxylase of Adrenal Chromaffin Granules: Structure and Function". Annual Review of Biochemistry. 57: 551–92. doi:10.1146/annurev.bi.57.070188.003003. PMID3052283.
^Miyagi, Y.; Matsumura, Y.; Sagami, H. (2007). "Human Geranylgeranyl Diphosphate Synthase is an Octamer in Solution". Journal of Biochemistry. 142 (3): 377–81. doi:10.1093/jb/mvm144. PMID17646172.
^Snook, Christopher F.; Tipton, Peter A.; Beamer, Lesa J. (2003). "Crystal Structure of GDP-Mannose Dehydrogenase: A Key Enzyme of Alginate Biosynthesis inP. Aeruginosa". Biochemistry. 42 (16): 4658–68. doi:10.1021/bi027328k. PMID12705829.
^ abKim, Sang Suk; Choi, I.-G.; Kim, Sung-Hou; Yu, Y. G. (1999). "Molecular cloning, expression, and characterization of a thermostable glutamate racemase from a hyperthermophilic bacterium, Aquifex pyrophilus". Extremophiles. 3 (3): 175–83. doi:10.1007/s007920050114. PMID10484173. S2CID709039.
^ abLundqvist, Tomas; Fisher, Stewart L.; Kern, Gunther; Folmer, Rutger H. A.; Xue, Yafeng; Newton, D. Trevor; Keating, Thomas A.; Alm, Richard A.; et al. (2007). "Exploitation of structural and regulatory diversity in glutamate racemases". Nature. 447 (7146): 817–22. Bibcode:2007Natur.447..817L. doi:10.1038/nature05689. PMID17568739. S2CID4408683.
^Sirover, Michael A (1999). "New insights into an old protein: The functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1432 (2): 159–84. doi:10.1016/S0167-4838(99)00119-3. PMID10407139.
^Kumagai, H; Sakai, H (1983). "A porcine brain protein (35 K protein) which bundles microtubules and its identification as glyceraldehyde 3-phosphate dehydrogenase". Journal of Biochemistry. 93 (5): 1259–69. doi:10.1093/oxfordjournals.jbchem.a134260. PMID6885722.
^ abDe Riel, Jon K.; Paulus, Henry (1978). "Subunit dissociation in the allosteric regulation of glycerol kinase from Escherichia coli. 2. Physical evidence". Biochemistry. 17 (24): 5141–6. doi:10.1021/bi00617a011. PMID215195.
^ abDe Riel, Jon K.; Paulus, Henry (1978). "Subunit dissociation in the allosteric regulation of glycerol kinase from Escherichia coli. 1. Kinetic evidence". Biochemistry. 17 (24): 5134–40. doi:10.1021/bi00617a010. PMID215194.
^ abDe Riel, Jon K.; Paulus, Henry (1978). "Subunit dissociation in the allosteric regulation of glycerol kinase from Escherichia coli. 3. Role in desensitization". Biochemistry. 17 (24): 5146–50. doi:10.1021/bi00617a012. PMID31903.
^ abBystrom, Cory E.; Pettigrew, Donald W.; Branchaud, Bruce P.; O'Brien, Patrick; Remington, S. James (1999). "Crystal Structures ofEscherichia coliGlycerol Kinase Variant S58→W in Complex with Nonhydrolyzable ATP Analogues Reveal a Putative Active Conformation of the Enzyme as a Result of Domain Motion". Biochemistry. 38 (12): 3508–18. doi:10.1021/bi982460z. PMID10090737.
^ abDeprez, Eric; Tauc, Patrick; Leh, Hervé; Mouscadet, Jean-François; Auclair, Christian; Brochon, Jean-Claude (2000). "Oligomeric States of the HIV-1 Integrase As Measured by Time-Resolved Fluorescence Anisotropy". Biochemistry. 39 (31): 9275–84. doi:10.1021/bi000397j. PMID10924120.
^Clarke, Anthony R.; Waldman, Adam D.B.; Munro, Ian; Holbrook, J.John (1985). "Changes in the state of subunit association of lactate dehydrogenase from Bacillus stearothermophilus". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 828 (3): 375–9. doi:10.1016/0167-4838(85)90319-X. PMID3986214.
^ abcdeClarke, Anthony R.; Waldman, Adam D.B.; Hart, Keith W.; John Holbrook, J. (1985). "The rates of defined changes in protein structure during the catalytic cycle of lactate dehydrogenase". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 829 (3): 397–407. doi:10.1016/0167-4838(85)90250-X. PMID4005269.
^Clarke, Anthony R.; Wigley, Dale B.; Barstow, David A.; Chia, William N.; Atkinson, Tony; Holbrook, J.John (1987). "A single amino acid substitution deregulates a bacterial lactate dehydrogenase and stabilizes its tetrameric structure". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 913 (1): 72–80. doi:10.1016/0167-4838(87)90234-2. PMID3580377.
^Cameron, Alexander D.; Roper, David I.; Moreton, Kathleen M.; Muirhead, Hilary; Holbrook, J.John; Wigley, Dale B. (1994). "Allosteric Activation in Bacillus stearothermophilus Lactate Dehydrogenase Investigated by an X-ray Crystallographic Analysis of a Mutant Designed to Prevent Tetramerization of the Enzyme". Journal of Molecular Biology. 238 (4): 615–25. doi:10.1006/jmbi.1994.1318. PMID8176749.
^ abcRoudiak, Stanislav G.; Shrader, Thomas E. (1998). "Functional Role of the N-Terminal Region of the Lon Protease fromMycobacterium smegmatis". Biochemistry. 37 (32): 11255–63. doi:10.1021/bi980945h. PMID9698372.
^ abcRudyak, Stanislav G.; Brenowitz, Michael; Shrader, Thomas E. (2001). "Mg2+-Linked Oligomerization Modulates the Catalytic Activity of the Lon (La) Protease from Mycobacterium smegmatis". Biochemistry. 40 (31): 9317–23. doi:10.1021/bi0102508. PMID11478899.
^Poole, Leslie B. (2005). "Bacterial defenses against oxidants: Mechanistic features of cysteine-based peroxidases and their flavoprotein reductases". Archives of Biochemistry and Biophysics. 433 (1): 240–54. doi:10.1016/j.abb.2004.09.006. PMID15581580.
^Aran, Martin; Ferrero, Diego S.; Pagano, Eduardo; Wolosiuk, Ricardo A. (2009). "Typical 2-Cys peroxiredoxins - modulation by covalent transformations and noncovalent interactions". FEBS Journal. 276 (9): 2478–93. doi:10.1111/j.1742-4658.2009.06984.x. hdl:11336/20656. PMID19476489. S2CID1698327.
^Bjørgo, Elisa; De Carvalho, Raquel Margarida Negrão; Flatmark, Torgeir (2001). "A comparison of kinetic and regulatory properties of the tetrameric and dimeric forms of wild-type and Thr427→Pro mutant human phenylalanine hydroxylase". European Journal of Biochemistry. 268 (4): 997–1005. doi:10.1046/j.1432-1327.2001.01958.x. PMID11179966.
^Phillips, Robert S.; Parniak, Michael A.; Kaufman, Seymour (1984). "Spectroscopic investigation of ligand interaction with hepatic phenylalanine hydroxylase: Evidence for a conformational change associated with activation". Biochemistry. 23 (17): 3836–42. doi:10.1021/bi00312a007. PMID6487579.
^Gotte, Giovanni; Laurents, Douglas V.; Libonati, Massimo (2006). "Three-dimensional domain-swapped oligomers of ribonuclease A: Identification of a fifth tetramer, pentamers and hexamers, and detection of trace heptameric, octameric and nonameric species". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1764 (1): 44–54. doi:10.1016/j.bbapap.2005.10.011. PMID16310422.
^ abGotte, Giovanni; Libonati, Massimo (1998). "Two different forms of aggregated dimers of ribonuclease A". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1386 (1): 106–112. doi:10.1016/S0167-4838(98)00087-9. PMID9675255.
^ abLibonati, M.; Gotte, G.; Vottariello, F. (2008). "A Novel Biological Actions Acquired by Ribonuclease Through Oligomerization". Current Pharmaceutical Biotechnology. 9 (3): 200–9. doi:10.2174/138920108784567308. PMID18673285.
^Kashlan, Ossama B.; Cooperman, Barry S. (2003). "Comprehensive Model for Allosteric Regulation of Mammalian Ribonucleotide Reductase: Refinements and Consequences†". Biochemistry. 42 (6): 1696–706. doi:10.1021/bi020634d. PMID12578384.
^Kashlan, Ossama B.; Scott, Charles P.; Lear, James D.; Cooperman, Barry S. (2002). "A Comprehensive Model for the Allosteric Regulation of Mammalian Ribonucleotide Reductase. Functional Consequences of ATP- and dATP-Induced Oligomerization of the Large Subunit†". Biochemistry. 41 (2): 462–74. doi:10.1021/bi011653a. PMID11781084.
^ abHohman, R.J.; Guitton, M.C.; Véron, M. (1984). "Purification of S-adenosyl-l-homocysteine hydrolase from Dictyostelium discoideum: Reversible inactivation by cAMP and 2′-deoxyadenosine". Archives of Biochemistry and Biophysics. 233 (2): 785–95. doi:10.1016/0003-9861(84)90507-1. PMID6091559.
^Addington, Adele K.; Johnson, David A. (1996). "Inactivation of Human Lung Tryptase: Evidence for a Re-Activatable Tetrameric Intermediate and Active Monomers". Biochemistry. 35 (42): 13511–8. doi:10.1021/bi960042t. PMID8885830.
^Fukuoka, Yoshihiro; Schwartz, Lawrence B. (2004). "Human β-Tryptase: Detection and Characterization of the Active Monomer and Prevention of Tetramer Reconstitution by Protease Inhibitors". Biochemistry. 43 (33): 10757–64. doi:10.1021/bi049486c. PMID15311937.
^Schechter, Norman M.; Choi, Eun-Jung; Selwood, Trevor; McCaslin, Darrell R. (2007). "Characterization of Three Distinct Catalytic Forms of Human Tryptase-β: Their Interrelationships and Relevance". Biochemistry. 46 (33): 9615–29. doi:10.1021/bi7004625. PMID17655281.
^Schechter, Norman M.; Eng, Grace Y.; Selwood, Trevor; McCaslin, Darrell R. (1995). "Structural Changes Associated with the Spontaneous Inactivation of the Serine Proteinase Human Tryptase". Biochemistry. 34 (33): 10628–38. doi:10.1021/bi00033a038. PMID7654717.
^Strik, Merel C. M.; Wolbink, Angela; Wouters, Dorine; Bladergroen, Bellinda A.; Verlaan, Angelique R.; van Houdt, Inge S.; Hijlkema, Sanne; Hack, C. Erik; et al. (2004). "Intracellular serpin SERPINB6 (PI6) is abundantly expressed by human mast cells and forms complexes with β-tryptase monomers". Blood. 103 (7): 2710–7. doi:10.1182/blood-2003-08-2981. PMID14670919.
^ abKozik, Andrzej; Potempa, Jan; Travis, James (1998). "Spontaneous inactivation of human lung tryptase as probed by size-exclusion chromatography and chemical cross-linking: Dissociation of active tetrameric enzyme into inactive monomers is the primary event of the entire process". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1385 (1): 139–48. doi:10.1016/S0167-4838(98)00053-3. PMID9630576.
^Alzani, R.; Cozzi, E.; Corti, A.; Temponi, M.; Trizio, D.; Gigli, M.; Rizzo, V. (1995). "Mechanism of suramin-induced deoligomerization of tumor necrosis factor .alpha". Biochemistry. 34 (19): 6344–50. doi:10.1021/bi00019a012. PMID7756262.
^ abcdJensen, Kaj Frank; Mygind, Bente (1996). "Different Oligomeric States are Involved in the Allosteric Behavior of Uracil Phosphoribosyltransferase from Escherichia Coli". European Journal of Biochemistry. 240 (3): 637–45. doi:10.1111/j.1432-1033.1996.0637h.x. PMID8856065.