Morpheein


Morpheeins are proteins that can form two or more different homo-oligomers, 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. 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. A mutation 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. The dice image 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.

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 allosteric regulation has similarities to and differences from other models. The concerted 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 takes into account that the protein may dissociate to interconvert between oligomers.

Implications for teaching about protein structure-function relationships

It is generally taught that a given amino acid sequence will have only one physiologically relevant 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, 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

ProteinExample speciesE.C.numberCAS numberAlternate oligomersEvidence
Acetyl-CoA carboxylase-1Gallus domesticusinactive dimer, active dimer, largerEffector molecules impact multimerization, Multiple/protein moonlighting functions
α-AcetylgalactosaminidaseBos taurusinactive monomer, active tetramerSubstrate binding/turnover impacts multimerization, Protein concentration dependent specific activity, Different assemblies have different activities, Conformationally distinct oligomeric forms.
Adenylosuccinate lyaseBacillus subtilismonomer, dimer, trimer, tetramerMutations shift the equilibrium of oligomers, Oligomer-dependent kinetic parameters, Protein concentration dependent molecular weight
Aristolochene synthasePenicillium roquefortimonomer, higher orderProtein concentration dependent specific activity
L-AsparaginaseLeptosphaeria michotiidimer, tetramer, inactive octamerSubstrate binding/turnover impacts multimerization
AspartokinaseEscherichia coli & monomer, dimer, tetramerMultiple/protein moonlighting functions, Conformationally distinct oligomeric forms
ATPase of the ABCA1 transporterHomo sapiensdimer, tetramerSubstrate binding/turnover impacts multimerization
Biotin— ligase holoenzyme synthetaseEscherichia colimonomer, dimerMultiple/protein moonlighting functions, Different assemblies have different activities
Chorismate mutaseEscherichia colidimer, trimer, hexamerConformationally distinct oligomeric forms
Citrate synthaseEscherichia colimonomer, dimer, trimer, tetramer, pentamer, hexamer, dodecamerSubstrate binding/turnover impacts multimerization, Characterized equilibrium of oligomers, Protein concentration dependent specific activity, pH-dependent oligomeric equilibrium
Cyanovirin-NNostoc ellipsosporummonomer and domain-swapped dimerCharacterized equilibrium of oligomers, Conformationally distinct oligomeric forms
3-oxoacid CoA-transferaseSus scrofa domesticadimer, tetramerChromatographically separable oligomers, Substrate might preferentially stabilize one form
Cystathionine beta-synthaseHomo sapiensmultiple - ranges from dimer to 16-merEffector 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 oxidasemonomers, dimers, higher-order oligomersOligomer-dependent kinetic parameters
Dihydrolipoamide dehydrogenaseSus scrofa domesticamonomer, two different dimer forms, tetramerMultiple/protein moonlighting functions, Different assemblies have different activities, pH-dependent oligomeric equilibrium, Conformationally distinct oligomeric forms
Dopamine beta-monooxygenaseBos taurusdimers, tetramersEffector molecules impact multimerization, Characterized equilibrium of oligomers, Oligomer-dependent kinetic parameters
Geranylgeranyl pyrophosphate synthase / FarnesyltranstransferaseHomo sapienshexamer, octamerEffector molecules impact multimerization
GDP-mannose 6-dehydrogenasePseudomonas aeruginosatrimer, 2 tetramers, and hexamerProtein concentration dependent specific activity, Kinetic hysteresis
Glutamate dehydrogenaseBos taurusactive & inactive hexamers, higher orderEffector molecules impact multimerization, Characterized equilibrium of oligomers
Glutamate racemaseMycobacterium tuberculosis, Escherichia coli, Bacillus subtilis, Aquifex pyrophilusmonomer, 2 dimers, tetramerMultiple/protein moonlighting functions, Characterized equilibrium of oligomers, Conformationally distinct oligomeric forms
Glyceraldehyde-3-phosphate dehydrogenaseOryctolagus cuniculas, Sus scrofa domesticamonomer, dimer, tetramer Characterized equilibrium of oligomers, Different assemblies have different activities-
Glycerol kinaseEscherichia colimonomer and 2 tetramersCharacterized equilibrium of oligomers, Conformationally distinct oligomeric forms, Effector functions by preventing domain motion
HIV-IntegraseHuman immunodeficiency virus-1monomer, dimer, tetramer, higher orderEffector molecules impact multimerization, Multiple/protein moonlighting functions, Different assemblies have different activities
HPr-Kinase/phosphataseBacillus subtilis, Lactobacillus casei, Mycoplasma pneumoniae, Staphylococcus xylosus/monomers, dimers, trimers, hexamersEffector molecules impact multimerization, Multiple/protein moonlighting functions, Different assemblies have different activities, pH-dependent oligomeric equilibrium
Lactate dehydrogenaseBacillus stearothermophilus2 dimers, tetramerEffector 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 proteaseEscherichia coli, Mycobacterium smegmatismonomer, dimer, trimer, tetramerEffector molecules impact multimerization, Substrate binding/turnover impacts multimerization, Protein concentration dependent specific activity, Kinetic hysteresis
Mitochondrial NAD+ Malic enzyme / malate dehydrogenase Homo sapiensmonomer, 2 dimers, tetramerEffector molecules impact multimerization, Mutations shift the equilibrium of oligomers, Kinetic hysteresis,
PeroxiredoxinsSalmonella typhimurium & 2 dimers, decamerConformationally distinct oligomeric forms, Different assemblies have different activities
Phenylalanine hydroxylaseHomo sapienshigh activity tetramer, low activity tetramerSubstrate binding/turnover impacts multimerization, Conformationally distinct oligomeric forms
Phosphoenolpyruvate carboxylaseEscherichia coli, Zea maysinactive dimer, active tetramerEffector molecules impact multimerization, Characterized equilibrium of oligomers, Kinetic hysteresis, Conformationally distinct oligomeric forms
PhosphofructokinaseBacillus stearothermophilus, Thermus thermophilusinactive dimer, active tetramerEffector molecules impact multimerization, Characterized equilibrium of oligomers
Polyphenol oxidaseAgaricus bisporus, Malus domestica, Lactuca sativa L.monomer, trimer, tetramer, octamer, dodecamerMultiple/protein moonlighting functions, Substrate binding/turnover impacts multimerization, Different assemblies have different activities, Kinetic hysteresis
Porphobilinogen synthaseDrosophila melanogaster, Danio reriodimer, hexamer, octamerPBGS is the prototype morpheein.
Pyruvate kinaseHomo sapiensactive and inactive dimers, active tetramer, monomer, trimer, pentamerConformationally distinct oligomeric forms
Ribonuclease ABos taurusmonomer, dimer, trimer, tetramer, hexamer, pentamer, higher orderMultiple/protein moonlighting functions, Different assemblies have different activities, Conformationally distinct oligomeric forms
Ribonucleotide reductaseMus musculustetramer, hexamerEffector molecules impact multimerization
S-adenosyl-L-homocysteine hydrolaseDictyostelium discoideumtetramer and otherEffector molecules impact multimerization
Biodegrative threonine dehydratase / threonine ammonia-lyaseEscherichia coli2 monomers, 2 tetramersEffector molecules impact multimerization, Characterized equilibrium of oligomers, Different assemblies have different activities
β-TryptaseHomo sapiensactive and inactive monomers, active and inactive tetramersProtein concentration dependent specific activity, Characterized equilibrium of oligomers
Tumor necrosis factor-alphaHomo sapiensmonomer, dimer, trimerDifferent assemblies have different activities
Uracil phosphoribosyltransferaseEscherichia colitrimer, pentamerEffector molecules impact multimerization, Substrate binding/turnover impacts multimerization, Different assemblies have different activities