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

作者：Soares Dinesh C^*; Barlow Paul N; Porteous David J; Devon Rebecca S

来源：Journal of Molecular Modeling, 2009, 15(2): 113-122.

DOI：10.1007/s00894-008-0381-1

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

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.

• 出版日期2009-2