Multimeric Proteins that Can Come Apart, Change Shape, and Reassemble Differently with Functional Consequences ‐ Morpheeins
Authors: Jaffe Eileen K. 
Published: April 2020

Herein we describe progress in a class of shape‐shifting proteins originally called morpheeins. These are homomultimers that can dissociate, change conformation in the dissociated state, and reassemble into a structurally and functionally distinct multimer. The original observation was of an octamer/dimer/dimer*/hexamer equilibrium wherein the conformational change was a hinge motion between folded domains of porphobilinogen synthase (PBGS). This phenomenon is established as a mechanism for allosteric regulation, druggable, and the structural basis for an inborn error of metabolism.

Many aspects of the original observations in the early 2000s were unexpected and peculiar; suggesting a structural metastability. At the time, vocabulary to describe such multi‐structural and multi‐functional protein dynamics were limited. We defined morpheeins as (homo‐multimeric) proteins that can come apart, change shape and reassemble differently with functional consequences. A Wikipedia page introduced a dice model of a morpheein (see image), and showed how multimer‐specific surface cavities can provide a general mechanism for drug action. In the beginning, multimeric proteins with more than one shape (in the absence of refolding) strongly defied the one sequence, one structure, one function paradigm. Two decades later, there are a growing number of examples of multimeric proteins with multiple structures and other proteins with multiple functions, many in the absence of any chemical modification or significant refolding.

The quaternary structure dynamics of PBGS have now been extensively described. Interestingly, one consequence of our focus on PBGS is that the literature began equated the specific properties of PBGS with all of the factors that must be in place for a protein to be classified as a morpheein. This is akin to saying that in order to be considered a mammal, an organism must have all of the characteristics of a rat. Herein, we set straight the definition of a morpheein; it is a protein that can come apart, change conformation in the dissociated state, and reassemble to a structurally and functionally distinct multimer. Alternate assemblies need not have different stoichiometries. Assembly interchange need not be triggered by ligand binding or catalysis. Functional difference need not be high activity and low activity (as in allosteric regulation of enzyme action), but can be moonlighting activities. Often the conformational change is a repositioning of folded domains relative to each other.

An excellent example of a moonlighting protein that appears to be a morpheein, and has also been called a transformer, is the VP40 protein of the Ebola virus. It too exists as dimers or hexamer or octamer and each alternate assembly is responsible for an alternate function in the viral life cycle. The individual assemblies are stabilized through interaction with a “third party”. A third likely example is the family of alternate assemblies of ribonucleotide reductase, whose timely interchange amongst alternate assemblies appears essential to the regulation of nucleotide pools. A fourth example is HIV integrase, whose three domains reposition relative to each other as part of viral integration. These examples will be illustrated.

Support or Funding Information

NIH grants 5R01 NS100081 and P30 CA006927

Dice image depicting an interchange of morpheein forms and a ligand that stabilizes one form.

Figure 1