Proteins with neomorphic moonlighting functions in disease

Abstract

One gene can encode multiple protein functions because of RNA splice variants, gene fusions during evolution, promiscuous enzyme activities, and moonlighting protein functions. In addition to these types of multifunctional proteins, in which both functions are considered "normal" functions of a protein, some proteins have been described in which a mutation or conformational change imparts a second function on a protein that is not a "normal" function of the protein. We propose to call these new functions "neomorphic moonlighting functions". The most common examples of neomorphic moonlighting functions are due to conformational changes that impart novel protein-protein interactions resulting in the formation of protein aggregates in Alzheimers, Parkinsons disease, and the systemic amyloidoses. Other changes that can result in a neomorphic moonlighting function include a mutation in SMAD4 that causes the protein to bind to new promoters and thereby alter gene transcription patterns, mutations in two isocitrate dehydrogenase isoforms that impart a new catalytic activity, and mutations in dihydrolipoamide dehydrogenase that activate a hidden protease activity. These neomorphic moonlighting functions were identified because of their connection to disease. In the cases described herein, the new functions cause cancers or severe neurological impairment, although in most cases the mechanism by which the new function leads to disease is unknown.

Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms

“…Although interventions that increase frataxin levels are suitable to reduce the gene silencing effect of a GAA expansion (11), compounds that specifically target stability, biogenesis, or catalytic function of FXN isoforms will be required to overcome the negative effects of I154F and W155R and probably other missense mutations as well. In general, our work emphasizes the potentially complex consequences of mutations in a multifunctional protein-frataxin being an excellent example among a growing number of such proteins (23). Understanding the intricate pathophysiology of defects in multifunctional proteins is relevant to our ability to make valid genotype-phenotype correlations and to develop effective treatments.…”

“…Thus, as observed for other multifunctional proteins (23,24), it is likely that FRDA missense mutations have complex biochemical effects that may contribute synergistically to the pathophysiology of Friedreich ataxia. To date, however, the functional consequences of such mutations have been studied almost exclusively in the context of FXN 81-210 (19,(25)(26)(27)).…”

Genome-scale identification and characterization of moonlighting proteins

“…We would like to note that some of the moonlighting proteins classified into the second or the third category are so-called neomorphic moonlighting proteins [19], which exhibit the secondary function due to a mutation or conformational change. Table 2 lists ten multi-functional and multi-domain proteins that were excluded by the Pfam domain search from the final list of moonlighting proteins.…”

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…Moonlighting proteins perform multiple independent functions originated not from alterations at gene level, but because of the consequence of altered cellular localization, oligomeric states or distinct interacting partners [4]. In the case of neomorphic moonlighting proteins [5], the physiological function can be converted into a pathological one due to interaction with a different partner protein in the pathological milieu. The prototype of these neomorphic moonlighting proteins is the Tubulin Polymerization Promoting Protein (TPPP/p25) [6].…”