Morpheeins are

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that can form two or more different homo-

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

s (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. Each oligomer has a finite number of subunits (

stoichiometry Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equal ...

). 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

prion Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...

s and amyloid. The different oligomers have distinct functionality. Interconversion of morpheein forms can be a structural basis for

allosteric regulation In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

, an idea noted many years ago, and later revived. A

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

that shifts the normal equilibrium of morpheein forms can serve as the basis for a conformational disease. Features of morpheeins can be exploited for

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...

. 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, 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.

Implications for allosteric regulation

The morpheein model of

has similarities to and differences from other models. 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. 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. Nonetheless, shortly after these theories were described, two groups of workers proposed what is now called the morpheein model and showed that it accounted for the regulatory behavior of glutamate dehydrogenase. Kurganov and Friedrich discussed models of this kind extensively in their books.

Implications for teaching about protein structure-function relationships

It is generally taught 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. The conformational differences that accompany conversion between oligomers may be similar to the protein motions necessary for function of some proteins. 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 Hysteresis is the dependence of the state of a system on its history. For example, a magnet may have more than one possible magnetic moment in a given magnetic field, depending on how the field changed in the past. Plots of a single component of ...

, and/or protein concentration dependent specific activity.

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. 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.

Table of proteins whose published behavior is consistent with that of a morpheein

{, class="wikitable sortable" , - ! Protein !! Example species !! EC number !! CAS number !! Alternate oligomers !! Evidence , - ,

Acetyl-CoA carboxylase Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is ...

-1 , , ''Gallus domesticus'' , , , , , , inactive dimer, active dimer, larger , , Effector molecules impact multimerization, Multiple/

protein moonlighting Protein moonlighting (or gene sharing) is a phenomenon by which a protein can perform more than one function. Ancestral moonlighting proteins originally possessed a single function but through evolution, acquired additional functions. Many prote ...

functions , - , α-Acetylgalactosaminidase , , ''Bos taurus'' , , , , , , inactive monomer, active tetramer , , Substrate binding/turnover impacts multimerization, Protein concentration dependent specific activity, Different assemblies have different activities, Conformationally distinct oligomeric forms. , - ,

Adenylosuccinate lyase Adenylosuccinate lyase (or adenylosuccinase) is an enzyme that in humans is encoded by the ADSL gene. Adenylosuccinate lyase converts adenylosuccinate to AMP and fumarate as part of the purine nucleotide cycle. ASL catalyzes two reactions in the ...

, , ''Bacillus subtilis'' , , , , , , monomer, dimer, trimer, tetramer , , Mutations shift the equilibrium of oligomers, Oligomer-dependent kinetic parameters, Protein concentration dependent molecular weight , - ,

Aristolochene synthase The enzyme aristolochene synthase (EC 4.2.3.9) catalyzes the chemical reaction : This enzyme belongs to the family of lyases, specifically those carbon-oxygen lyases acting on phosphates. The systematic name of this enzyme class is (2''E'',6'' ...

, , ''Penicillium roqueforti'' , , , , , , monomer, higher order , , Protein concentration dependent specific activity , - , L-

Asparaginase Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). It is given by injection into a vein, muscl ...

, , ''Leptosphaeria michotii'' , , , , , , dimer, tetramer, inactive octamer , , Substrate binding/turnover impacts multimerization , - ,

Aspartokinase Aspartate kinase or aspartokinase (AK) is an enzyme that catalyzes the phosphorylation of the amino acid aspartate. This reaction is the first step in the biosynthesis of three other amino acids: methionine, lysine, and threonine, known as the " ...

, , ''Escherichia coli'' , , & , , , , monomer, dimer, tetramer , , Multiple/

functions, Conformationally distinct oligomeric forms , - ,

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...

of the ABCA1 transporter , , ''Homo sapiens'' , , , , , , dimer, tetramer , , Substrate binding/turnover impacts multimerization , - ,

Biotin—(acetyl-CoA-carboxylase) ligase In enzymology, a biotin— cetyl-CoA-carboxylaseligase () is an enzyme that catalyzes the chemical reaction :ATP + biotin + apo- cetyl-CoA:carbon-dioxide ligase (ADP-forming)\rightleftharpoons AMP + diphosphate + cetyl-CoA:carbon-dioxide ligase ...

holoenzyme synthetase , , ''Escherichia coli'' , , , , , , monomer, dimer , , Multiple/

functions, Different assemblies have different activities , - ,

Chorismate mutase In enzymology, chorismate mutase () is an enzyme that catalyzes the chemical reaction for the conversion of chorismate to prephenate in the pathway to the production of phenylalanine and tyrosine, also known as the shikimate pathway. Hence, this ...

, , ''Escherichia coli'' , , , , , , dimer, trimer, hexamer , , Conformationally distinct oligomeric forms , - , Citrate synthase , , ''Escherichia coli'' , , , , , , monomer, dimer, trimer, tetramer, pentamer, hexamer, dodecamer , , Substrate binding/turnover impacts multimerization, Characterized equilibrium of oligomers, Protein concentration dependent specific activity, pH-dependent oligomeric equilibrium , - ,

Cyanovirin-N Cyanovirin-N (CV-N) is a protein produced by the cyanobacterium '' Nostoc ellipsosporum'' that displays virucidal activity against several viruses, including human immunodeficiency virus (HIV). The virucidal activity of CV-N is mediated through s ...

, , ''Nostoc ellipsosporum'' , , , , , , monomer and domain-swapped dimer , , Characterized equilibrium of oligomers, Conformationally distinct oligomeric forms , - ,

3-oxoacid CoA-transferase In enzymology, a 3-oxoacid CoA-transferase () is an enzyme that catalyzes the chemical reaction :succinyl-CoA + a 3-oxo acid \rightleftharpoons succinate + a 3-oxoacyl-CoA Thus, the two substrates of this enzyme are succinyl-CoA and 3-oxo acid ...

, , ''Sus scrofa domestica'' , , , , , , dimer, tetramer , , Chromatographically separable oligomers, Substrate might preferentially stabilize one form , - , Cystathionine β-synthase , , ''Homo sapiens'' , , , , , , multiple - ranges from dimer to 16-mer , , Effector molecules impact multimerization, Mutations shift the equilibrium of oligomers, Different assemblies have different activities, disease-causing mutations at sites distant from active site , - , D-amino acid oxidase , , , , , , , , monomers, dimers, higher-order oligomers , , Oligomer-dependent kinetic parameters , - ,

Dihydrolipoamide dehydrogenase Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the ''DLD'' gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide. Dihydrolipoamid ...

, , ''Sus scrofa domestica'' , , , , , , monomer, two different dimer forms, tetramer , , Multiple/

functions, Different assemblies have different activities, pH-dependent oligomeric equilibrium, Conformationally distinct oligomeric forms , - ,

Dopamine β-monooxygenase Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme () that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine. The three substrates of ...

, , ''Bos taurus'' , , , , , , dimers, tetramers , , Effector molecules impact multimerization, Characterized equilibrium of oligomers, Oligomer-dependent kinetic parameters , - , Geranylgeranyl pyrophosphate synthase / Farnesyltranstransferase , , ''Homo sapiens'' , , , , , , hexamer, octamer, , Effector molecules impact multimerization , - , GDP-mannose 6-dehydrogenase , , ''Pseudomonas aeruginosa'' , , , , , , trimer, 2 tetramers, and hexamer , , Protein concentration dependent specific activity, Kinetic hysteresis , - , Glutamate dehydrogenase , , ''Bos taurus'' , , , , , , active & inactive hexamers, higher order , , Effector molecules impact multimerization, Characterized equilibrium of oligomers , - ,

Glutamate racemase In enzymology, glutamate racemase (MurI with a capital ''i'') () is an enzyme that catalysis, catalyzes the chemical reaction :L-glutamate \rightleftharpoons D-glutamate Hence, this enzyme RacE has one substrate (biochemistry), substrate, glutam ...

, , ''Mycobacterium tuberculosis, Escherichia coli, Bacillus subtilis, Aquifex pyrophilus'' , , , , , , monomer, 2 dimers, tetramer , , Multiple/

functions, Characterized equilibrium of oligomers, Conformationally distinct oligomeric forms , - ,

Glyceraldehyde-3-phosphate dehydrogenase Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establishe ...

, , ''Oryctolagus cuniculas, Sus scrofa domestica'' , , , , , , monomer, dimer, tetramer Characterized equilibrium of oligomers, Different assemblies have different activities , - ,

Glycerol kinase Glycerol kinase, encoded by the gene ''GK'', is a phosphotransferase enzyme involved in triglycerides and glycerophospholipids synthesis. Glycerol kinase catalyzes the transfer of a phosphate from ATP to glycerol thus forming glycerol 3-phosph ...

, , ''Escherichia coli'' , , , , , , monomer and 2 tetramers , , Characterized equilibrium of oligomers, Conformationally distinct oligomeric forms, Effector functions by preventing domain motion , - , HIV-

Integrase Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...

, , Human immunodeficiency virus-1 , , , , , , monomer, dimer, tetramer, higher order , , Effector molecules impact multimerization, Multiple/

functions, Different assemblies have different activities , - , HPr-Kinase/phosphatase , , ''Bacillus subtilis, Lactobacillus casei, Mycoplasma pneumoniae, Staphylococcus xylosus'' , , / , , , , monomers, dimers, trimers, hexamers , , Effector molecules impact multimerization, Multiple/

functions, Different assemblies have different activities, pH-dependent oligomeric equilibrium , - , Lactate dehydrogenase , , ''Bacillus stearothermophilus'' , , , , , , 2 dimers, tetramer , , Effector molecules impact multimerization, Characterized equilibrium of oligomers, Protein concentration dependent specific activity, Mutations shift the equilibrium of oligomers, Oligomer-dependent kinetic parameters, Conformationally distinct oligomeric forms , - , Lon protease , , ''Escherichia coli, Mycobacterium smegmatis'' , , , , , , monomer, dimer, trimer, tetramer , , Effector molecules impact multimerization, Substrate binding/turnover impacts multimerization, Protein concentration dependent specific activity, Kinetic hysteresis , - , Mitochondrial NAD(P)⁺ Malic enzyme / malate dehydrogenase (oxaloacetate-decarboxylating) (NADP⁺) , , ''Homo sapiens'' , , , , , , monomer, 2 dimers, tetramer , , Effector molecules impact multimerization, Mutations shift the equilibrium of oligomers, Kinetic hysteresis, , - ,

Peroxiredoxin Peroxiredoxins (Prxs, ; HGNC root symbol ''PRDX'') are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX ...

s , , ''Salmonella typhimurium'' , , & , , , , 2 dimers, decamer , , Conformationally distinct oligomeric forms, Different assemblies have different activities , - , Phenylalanine hydroxylase , , ''Homo sapiens'' , , , , , , high activity tetramer, low activity tetramer , , Substrate binding/turnover impacts multimerization, Conformationally distinct oligomeric forms , - , Phosphoenolpyruvate carboxylase , , ''Escherichia coli, Zea mays'' , , , , , , inactive dimer, active tetramer , , Effector molecules impact multimerization, Characterized equilibrium of oligomers, Kinetic hysteresis, Conformationally distinct oligomeric forms , - ,

Phosphofructokinase Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis. Function The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...

, , ''Bacillus stearothermophilus, Thermus thermophilus'' , , , , , , inactive dimer, active tetramer , , Effector molecules impact multimerization, Characterized equilibrium of oligomers , - ,

Polyphenol oxidase Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule. PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...

, , ''Agaricus bisporus, Malus domestica, Lactuca sativa L.'' , , , , , , monomer, trimer, tetramer, octamer, dodecamer , , Multiple/

functions, Substrate binding/turnover impacts multimerization, Different assemblies have different activities, Kinetic hysteresis , - , Porphobilinogen synthase , , ''Drosophila melanogaster, Danio rerio'' , , , , , , dimer, hexamer, octamer , , PBGS is the prototype morpheein. , - ,

Pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...

, , ''Homo sapiens'' , , , , , , active and inactive dimers, active tetramer, monomer, trimer, pentamer , , Conformationally distinct oligomeric forms , - , Ribonuclease A , , ''Bos taurus'' , , , , , , monomer, dimer, trimer, tetramer, hexamer, pentamer, higher order , , Multiple/

functions, Different assemblies have different activities, Conformationally distinct oligomeric forms , - ,

Ribonucleotide reductase Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of th ...

, , ''Mus musculus'' , , , , , , tetramer, hexamer , , Effector molecules impact multimerization , - , ''S''-adenosyl-L-homocysteine hydrolase , , ''Dictyostelium discoideum'' , , , , , , tetramer and other , , Effector molecules impact multimerization , - , Biodegrative threonine dehydratase / threonine ammonia-lyase , , ''Escherichia coli'' , , , , , , 2 monomers, 2 tetramers , , Effector molecules impact multimerization, Characterized equilibrium of oligomers, Different assemblies have different activities , - , β- Tryptase , , ''Homo sapiens'' , , , , , , active and inactive monomers, active and inactive tetramers , , Protein concentration dependent specific activity, Characterized equilibrium of oligomers , - ,

Tumor necrosis factor-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

, , ''Homo sapiens'' , , , , , , monomer, dimer, trimer , , Different assemblies have different activities , - ,

Uracil phosphoribosyltransferase Uracil phosphoribosyltransferase is an enzyme which creates UMP from uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds t ...

, , ''Escherichia coli'' , , , , , , trimer, pentamer{{cite journal , doi=10.1111/j.1432-1033.1996.0637h.x , title=Different Oligomeric States are Involved in the Allosteric Behavior of Uracil Phosphoribosyltransferase from Escherichia Coli , year=1996 , last1=Jensen , first1=Kaj Frank , last2=Mygind , first2=Bente , journal=European Journal of Biochemistry , volume=240 , issue=3 , pages=637–45 , pmid=8856065 , , Effector molecules impact multimerization, Substrate binding/turnover impacts multimerization, Different assemblies have different activities

References

Proteins