Document Type


Peer Reviewed


Publication Date


NLM Title Abbreviation

PLoS One

Journal/Book/Conference Title

PLoS One

PubMed ID


DOI of Published Version


Total Pages



Polyglutamine (polyQ) tracts in regulatory proteins are extremely polymorphic. As functional elements under selection for length, triplet repeats are prone to DNA replication slippage and indel mutations. Many polyQ tracts are also embedded within intrinsically disordered domains, which are less constrained, fast evolving, and difficult to characterize. To identify structural principles underlying polyQ tracts in disordered regulatory domains, here I analyze deep evolution of metazoan Notch polyQ tracts, which can generate alleles causing developmental and neurogenic defects. I show that Notch features polyQ tract turnover that is restricted to a discrete number of conserved "polyQ insertion slots". Notch polyQ insertion slots are: (i) identifiable by an amphipathic "slot leader" motif; (ii) conserved as an intact C-terminal array in a 1-to-1 relationship with the N-terminal solenoid-forming ankyrin repeats (ARs); and (iii) enriched in carboxamide residues (Q/N), whose sidechains feature dual hydrogen bond donor and acceptor atoms. Correspondingly, the terminal loop and β-strand of each AR feature conserved carboxamide residues, which would be susceptible to folding interference by hydrogen bonding with residues outside the ARs. I thus suggest that Notch polyQ insertion slots constitute an array of AR interference elements (ARIEs). Notch ARIEs would dynamically compete with the delicate serial folding induced by adjacent ARs. Huntingtin, which harbors solenoid-forming HEAT repeats, also possesses a similar number of polyQ insertion slots. These results suggest that intrinsically disordered interference arrays featuring carboxamide and polyQ enrichment may constitute coupled proteodynamic modulators of solenoids.


OAfund, Animals, Drosophila Proteins, Drosophila melanogaster, Evolution, Molecular, Huntingtin Protein, Hydrogen Bonding, Models, Genetic, Models, Molecular, Peptides, Protein Domains, Protein Folding, Protein Structure, Secondary, Receptors, Notch, Repetitive Sequences, Nucleic Acid, Sequence Homology, Amino Acid

Journal Article Version

Version of Record

Published Article/Book Citation

PLoS ONE 12(3): e0174253. https://doi. org/10.1371/journal.pone.0174253


Copyright (c) 2017 Albert J. Erives

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