Sequence Context Influences the Structure and Aggregation Behavior of a PolyQ Tract.
Expansions of polyglutamine (polyQ) tracts in nine different proteins cause a family of neurodegenerative disorders called polyQ diseases. Because polyQ tracts are potential therapeutic targets for these pathologies there is great interest in characterizing the conformations that they adopt and in understanding how their aggregation behavior is influenced by the sequences flanking them. We used solution NMR to study at single-residue resolution a 156-residue proteolytic fragment of the androgen receptor that contains a polyQ tract associated with the disease spinobulbar muscular atrophy, also known as Kennedy disease. Our findings indicate that a Leu-rich region preceding the polyQ tract causes it to become α-helical and appears to protect the protein against aggregation, which represents a new, to our knowledge, mechanism by which sequence context can minimize the deleterious properties of these repetitive regions. Our results have implications for drug discovery for polyQ diseases because they suggest that the residues flanking these repetitive sequences may represent viable therapeutic targets.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Bahareh
B
Eftekharzadeh
CERM and Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Florence, Italy.
Alessandro
A
Piai
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Giulio
G
Chiesa
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Daniele
D
Mungianu
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Jesús
J
García
CERM and Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Florence, Italy.
Roberta
R
Pierattelli
CERM and Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Florence, Italy.
Isabella C
IC
Felli
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; ICREA, Barcelona, Spain. Electronic address: xavier.salvatella@irbbarcelona.org.
Xavier
X
Salvatella
D000595:Amino Acid Sequence; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000378:metabolism; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002942:Circular Dichroism; D000067493:Dynamic Light Scattering; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D055503:Protein Multimerization / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D066244:Proton Magnetic Resonance Spectroscopy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine