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Journal of Molecular Modeling

, Volume 15, Issue 2, pp 113–122 | Cite as

An interrupted beta-propeller and protein disorder: structural bioinformatics insights into the N-terminus of alsin

  • Dinesh C. SoaresEmail author
  • Paul N. Barlow
  • David J. Porteous
  • Rebecca S. Devon
Original Paper

Abstract

Defects in the human ALS2 gene, which encodes the 1,657-amino-acid residue protein alsin, are linked to several related motor neuron diseases. We created a structural model for the N-terminal 690-residue region of alsin through comparative modelling based on regulator of chromosome condensation 1 (RCC1). We propose that this alsin region contains seven RCC1-like repeats in a seven-bladed beta-propeller structure. The propeller is formed by a double clasp arrangement containing two segments (residues 1–218 and residues 525–690). The 306-residue insert region, predicted to lie within blade 5 and to be largely disordered, is poorly conserved across species. Surface patches of evolutionary conservation probably indicate locations of binding sites. Both disease-causing missense mutations—Cys157Tyr and Gly540Glu—are buried in the propeller and likely to be structurally disruptive. This study aids design of experimental studies by highlighting the importance of construct length, will enhance interpretation of protein–protein interactions, and enable rational site-directed mutagenesis.

Keywords

Alsin Beta-propeller Comparative modeling Fold recognition Protein disorder RCC1-repeat 

Notes

Acknowledgements

We would like to thank Dr. Andrew F. Coulson for critical reading of the manuscript, and Dr. Alice J. Walmesley and Prof. Lindsay Sawyer for helpful discussions. D.C.S. acknowledges funding from a Strategic Research Development Grant. The model co-ordinates are available from D.C.S. upon request.

Supplementary material

894_2008_381_MOESM1_ESM.pdf (906 kb)
ESM 1 (PDF 906 KB).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Dinesh C. Soares
    • 1
    • 2
    Email author
  • Paul N. Barlow
    • 2
    • 3
  • David J. Porteous
    • 1
  • Rebecca S. Devon
    • 1
  1. 1.Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General HospitalUniversity of EdinburghEdinburghUK
  2. 2.School of ChemistryUniversity of EdinburghEdinburghUK
  3. 3.Institute of Structural and Molecular BiologyUniversity of EdinburghEdinburghUK

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