ABSTRACT
Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA.
Subject(s)
Bulbo-Spinal Atrophy, X-Linked/genetics , Peptides/chemistry , Protein Conformation, alpha-Helical/genetics , Receptors, Androgen/chemistry , Transcription Factors/chemistry , Bulbo-Spinal Atrophy, X-Linked/pathology , Circular Dichroism , Glutamine/chemistry , Humans , Hydrogen/chemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Dynamics Simulation , Mutation , Protein Aggregates/genetics , Receptors, Androgen/genetics , Transcription Factors/geneticsABSTRACT
Neuroimaging studies in amyotrophic lateral sclerosis (ALS) investigating movements of the hands have in general found increased activation compared to healthy controls, which has been interpreted in terms of cortical adaptation as a result of corticospinal tract damage. Here, we investigated brain activations to vertical tongue movements using functional MRI at 3 tesla. Whereas healthy controls, patients with Kennedy syndrome, and ALS patients without bulbar involvement showed robust and indistinguishable activations in pre- and postcentral areas and the thalamus, ALS patients with bulbar involvement showed a significant decrease of cortical activity and missing thalamic activity. This decrease stands in marked contrast to the increase of activity observed in ALS patients when performing limb movements. We discuss these divergent findings with regard to the different physiological properties of tongue and limb movements. These findings may also help to explain the faster time-course of the disease in patients with bulbar involvement.