Wrangling Shape-Shifting Morpheeins to Tackle Disease and Approach Drug Discovery

Abstract

Homo-multimeric proteins that can come apart, change shape, and reassemble differently with functional consequences have been called morpheeins and/or transformers; these provide a largely unexplored context for understanding disease and developing allosteric therapeutics. This article describes such proteins within the context of protein structure dynamics, provides one detailed example related to an inborn error of metabolism and potential herbicide development, and describes the context for applying these ideas for understanding disease and designing bioactive molecules, such as therapeutics.

Proteomes Are of Proteoforms: Embracing the Complexity

“…This does not include gene fusions, multiple RNA splice variants, or pleiotropic effects, although these can also modify the function(s) of a given canonical protein. Another term, ‘morpheeins,’ is used to describe proteins that change shape and assemble in alternate configurations with different functions [ 34 , 35 ]. Noncanonical open reading frames (ORF) have been the subject of intense investigation since their discovery, and their functional products are proving quite important [ 36 ].…”

Naturally occurring cancer-associated mutations disrupt oligomerization and activity of protein arginine methyltransferase 1 (PRMT1)

“…A morpheein is a protein in which lower oligomeric forms are capable of adopting distinct conformations, which give rise to structurally distinct higher-order oligomers with distinct functions ( 82 , 83 , 84 ). Some of the characteristics of morpheeins are hinted at in the results of this study.…”

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

“…Nevertheless, the mechanism of action of pharmacological chaperones is not completely understood, and other mechanistic scenarios have been put forward [ 183 , 184 ]. Considering that mutations may change the distribution of the conformational ensemble, e.g., by enhancing the relative proportion of less active conformers with respect to the active conformation, specific ligand binding to the active conformers may shift the equilibrium towards the accumulation of these functional conformers in the mutant protein, increasing its activity [ 132 , 183 , 185 ]. Moreover, several binding mechanisms have been proposed, but, commonly, they describe a specific interaction of the pharmacological chaperones in an explicit location of the target protein.…”

“…The conformational variability of HMBS, which explores several enzyme intermediates along the elongation process (E (holo) and ES 1–4 ; Figure 3 ), is clearly altered in p.Arg173Trp, concomitant with a defective elongation mechanism. This mutant may be a target for pharmacological chaperones that specifically bind to the ES 2 conformer, hopefully shifting the equilibrium to a repopulated conformer ensemble, bypassing the elongation halt towards ES 3 [ 132 , 183 , 185 ]. The effectiveness of high-resolution mass spectrometry to separate and identify the intermediates [ 76 ], and its adaptability to high-throughput screening, readily encourages the search for these kind of pharmacological chaperones for specific AIP mutants.…”