Intrinsically unstructured proteins evolve by repeat expansion

Main point: the genetic instability of repetitive regions combined with the structurally and functionally permissive nature of unstructured proteins powers the extension and possible functional expansion of disordered proteins

• The functions fulfilled by disordered proteins depend on the lack of structure, so disorder is advantageous and evolutionarily stable for these proteins (pg 847)

• The fraction of the genome encoding for disordered proteins increases with organism complexity (pg 847)

• Paper discussion: observation that compositionally biased and low complexity regions, often found in disordered proteins, evolve rapidly by: repeat expansion, replication slippage, and substitution mutations; these repetitive segments are functionally indispensable and their three alternative evolutionary routes of expansion are probably driven by positive selection

[edit] 1 Tandem repeats

• Tandem arrays of sequence repeats are abundant in all genomes studied so far
• Classified by length of repeat unit (pg 847):
  • Satellite (several thousand bp)
  • Minisatellite (10-1000 bp)
  • Microsatellite (1-10 bp)
• Evolved rapidly by: mitotic replication or meiotic recombination events (geneconversion and unequal crossover)
• Coding micro- and minisatellites have a high level of interspecies variation and polymorphism and can rapidly generate new functional variants
• Coding microsatellites are implicated mostly in neurodegenerative diseases but can also carry function
• Coding minisatellites correspond to structural units arranged in tandem and constitute building blocks of stable secondary or supersecondary elements
• Longer repeats encode for domains like autonomous folding units

• large fraction of disordered proteins contains significant repeat regions, exceeding the frequency of any other group of proteins

Three different evolutionary types:

• Type I: regions where repeats generated by tandem duplications do not undergo diversification
• Type II: regions where repeats diversify due to their differential localization within the sequence or sequential changes, specialize in binding different ligands and become functionally non-redundant in time
• Type III: regions where repeats acquire novel functions as a result of expansion

[edit] 2 Examples

• Salivary proline-rich proteins (PRP), recognition (type I)
• Titin PEVK domain, entropic chain (type I)
• Fibronectin-binging protein A (type I)
• Involucrin, Q-region, transglutaminase cross-linking (type I)
• Neurofilament-H, KSP domain, entropic sidearm (type I)
• Prion protein, octarepeats, copper binding (type III)
• Sry, transactivator domain, complex assembly (type I or II)
• Tau protein, imperfect repeats, microtubule binding and polymerization (type I)

[edit] 3 Conclusion

• Repeat regions in disordered sequences carry important functions
• The inherent genetic instability and structural/functional permissibility of disordered proteins encourages rapid and advantageous evolutionary changes