title: Unveiling transient protein-protein interactions that modulate inhibition of alpha-synuclein aggregation by beta-synuclein, a pre-synaptic protein that co-localizes with alpha-synuclein.
abstract: Pathology in Parkinson's disease is linked to self-association of α-Synuclein (αS) into pathogenic oligomeric species and highly ordered amyloid fibrils. Developing effective therapeutic strategies against this debilitating disease is critical and βS, a pre-synaptic protein that co-localizes with αS, can act as an inhibitor of αS assembly. Despite the potential importance of βS as an inhibitor of αS, the nature, location and specificity of the molecular interactions between these two proteins is unknown. Here we use NMR paramagnetic relaxation enhancement experiments, to demonstrate that βS interacts directly with αS in a transient dimer complex with high specificity and weak affinity. Inhibition of αS by βS arises from transient αS/βS heterodimer species that exist primarily in head- to- tail configurations while αS aggregation arises from a more heterogeneous and weaker range of transient interactions that include both head-to-head and head-to-tail configurations. Our results highlight that intrinsically disordered proteins can interact directly with one another at low affinity and that the transient interactions that drive inhibition versus aggregation are distinct by virtue of their plasticity and specificity.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Janowska
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Kuen-Phon
authors.initials: KP
authors.lastname: Wu
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D008954:Models, Biological; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D021381:Protein Transport; D016415:Sequence Alignment; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*; D051846:beta-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D051846:beta-Synuclein