An interrupted beta-propeller and protein disorder: structural bioinformatics insights into the N-terminus of alsin.
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.
Soares
Dinesh C
DC
Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh EH42XU, UK. Dinesh.Soares@ed.ac.uk
Barlow
Paul N
PN
Porteous
David J
DJ
Devon
Rebecca S
RS
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid
C438187:ALS2 protein, human; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C062521:RCC1 protein, human; D003545:Cysteine; D005998:Glycine