A Bioinformatics Method for Identifying Q/N-Rich Prion-Like Domains in Proteins

  • Eric D. Ross
  • Kyle S. MacLea
  • Charles Anderson
  • Asa Ben-Hur
Part of the Methods in Molecular Biology book series (MIMB, volume 1017)


Numerous proteins contain domains that are enriched in glutamine and asparagine residues, and aggregation of some of these proteins has been linked to both prion formation in yeast and a number of human diseases. Unfortunately, predicting whether a given glutamine/asparagine-rich protein will aggregate has proven difficult. Here we describe a recently developed algorithm designed to predict the aggregation propensity of glutamine/asparagine-rich proteins. We discuss the basis for the algorithm, its limitations, and usage of recently developed online and downloadable versions of the algorithm.

Key words

Yeast Prion Amyloid Bioinformatics 



This work was supported by a National Science Foundation grant (MCB-1023771) to E.D.R.


  1. 1.
    Michelitsch MD, Weissman JS (2000) A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc Natl Acad Sci USA 97(22):11910–11915PubMedCrossRefGoogle Scholar
  2. 2.
    MacLea KS, Ross ED (2011) Strategies for identifying new prions in yeast. Prion 5(4):263–268PubMedGoogle Scholar
  3. 3.
    King OD, Gitler AD, Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 1462:61–80. doi: 10.1016/j.brainres.2012.01.016 PubMedCrossRefGoogle Scholar
  4. 4.
    Da Cruz S, Cleveland DW (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 21(6):904–919. doi: 10.1016/j.conb.2011.05.029 PubMedCrossRefGoogle Scholar
  5. 5.
    Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Mojsilovic-Petrovic J, Panossian S, Kim CE, Frackelton EC, Solski JA, Williams KL, Clay-Falcone D, Elman L, McCluskey L, Greene R, Hakonarson H, Kalb RG, Lee VM, Trojanowski JQ, Nicholson GA, Blair IP, Bonini NM, Van Deerlin VM, Mourelatos Z, Shorter J, Gitler AD (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21(13):2899–2911. doi: 10.1093/hmg/dds116 PubMedCrossRefGoogle Scholar
  6. 6.
    Couthouis J, Hart MP, Shorter J, Dejesus-Hernandez M, Erion R, Oristano R, Liu AX, Ramos D, Jethava N, Hosangadi D, Epstein J, Chiang A, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Solski JA, Williams KL, Mojsilovic-Petrovic J, Ingre C, Boylan K, Graff-Radford NR, Dickson DW, Clay-Falcone D, Elman L, McCluskey L, Greene R, Kalb RG, Lee VM, Trojanowski JQ, Ludolph A, Robberecht W, Andersen PM, Nicholson GA, Blair IP, King OD, Bonini NM, Van Deerlin V, Rademakers R, Mourelatos Z, Gitler AD (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA 108:20881–20890. doi: 10.1073/pnas.1109434108 PubMedCrossRefGoogle Scholar
  7. 7.
    Neumann M, Bentmann E, Dormann D, Jawaid A, DeJesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR (2011) FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134(Pt 9):2595–2609. doi: 10.1093/brain/awr201 PubMedCrossRefGoogle Scholar
  8. 8.
    Ross ED, Baxa U, Wickner RB (2004) Scrambled prion domains form prions and amyloid. Mol Cell Biol 24(16):7206–7213PubMedCrossRefGoogle Scholar
  9. 9.
    Ross ED, Edskes HK, Terry MJ, Wickner RB (2005) Primary sequence independence for prion formation. Proc Natl Acad Sci USA 102(36):12825–12830PubMedCrossRefGoogle Scholar
  10. 10.
    Harrison PM, Gerstein M (2003) A method to assess compositional bias in biological sequences and its application to prion-like glutamine/asparagine-rich domains in eukaryotic proteomes. Genome Biol 4(6):R40PubMedCrossRefGoogle Scholar
  11. 11.
    Sondheimer N, Lindquist S (2000) Rnq1: an epigenetic modifier of protein function in yeast. Mol Cell 5(1):163–172PubMedCrossRefGoogle Scholar
  12. 12.
    Alberti S, Halfmann R, King O, Kapila A, Lindquist S (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137(1):146–158PubMedCrossRefGoogle Scholar
  13. 13.
    Toombs JA, McCarty BR, Ross ED (2010) Compositional determinants of prion formation in yeast. Mol Cell Biol 30(1):319–332PubMedCrossRefGoogle Scholar
  14. 14.
    Ross ED, Toombs JA (2010) The effects of amino acid composition on yeast prion formation and prion domain interactions. Prion 4(2):60–65PubMedCrossRefGoogle Scholar
  15. 15.
    Toombs JA, Petri M, Paul KR, Kan GY, Ben-Hur A, Ross ED (2012) De novo design of synthetic prion domains. Proc Natl Acad Sci USA 109(17):6519–6524PubMedCrossRefGoogle Scholar
  16. 16.
    Prilusky J, Felder CE, Zeev-Ben-Mordehai T, Rydberg EH, Man O, Beckmann JS, Silman I, Sussman JL (2005) FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21(16):3435–3438PubMedCrossRefGoogle Scholar
  17. 17.
    Chou PY, Fasman GD (1974) Conformational parameters for amino acids in helical, beta-sheet, and random coil regions calculated from proteins. Biochemistry 13(2):211–222PubMedCrossRefGoogle Scholar
  18. 18.
    Crow ET, Du Z, Li L (2011) A small, glutamine-free domain propagates the [SWI(+)] prion in budding yeast. Mol Cell Biol 31(16):3436–3444. doi: 10.1128/MCB.05338-11 PubMedCrossRefGoogle Scholar
  19. 19.
    Kim HJ, Kim NC, Wang YD, et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, New York 2013

Authors and Affiliations

  • Eric D. Ross
    • 1
    • 2
  • Kyle S. MacLea
    • 3
  • Charles Anderson
    • 4
  • Asa Ben-Hur
    • 4
  1. 1.Department of BiochemistryColorado State UniversityFort CollinsUSA
  2. 2.Department of Molecular BiologyColorado State UniversityFort CollinsUSA
  3. 3.Department of Biochemistry and Molecular BiologyColorado State UniversityFort CollinsUSA
  4. 4.Department of Computer ScienceColorado State UniversityFort CollinsUSA

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