Megan Maurer - Huntingtin N-terminal monomeric and multimeric structures destabilized by covalent modification of heteroatomic residues

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      Publication Details (including relevant citation   information):

    1.    James R. Arndt; Samaneh G. Kondalaji, Megan M. Maurer, Arlo Parker, Justin Legleiter, Stephen J. Valentine. "Huntingtin N-terminal monomeric and multimeric structures destabilized by covalent modification of heteroatomic residues." Biochemistry (2015). DOI: 10.1021/acs.biochem.5b00478

     

      Abstract:

      Early-stage oligomer formation of the huntingtin protein may be   driven by self-association of the seventeen-residue amphipathic   α-helix at the protein’s N-terminus (Nt17). Oligomeric structures   have been implicated in neuronal toxicity and may represent   important neurotoxic species in Huntington’s disease. Therefore,   a residue-specific structural characterization of Nt17 is crucial   to understanding and potentially inhibiting oligomer formation.   Native electrospray ion mobility spectrometry-mass spectrometry   (IMS-MS) techniques and molecular dynamics simulations (MDS),   have been applied to study coexisting monomer and multimer   conformations of Nt17, independent of the remainder of huntingtin   exon 1. MDS suggests gas-phase monomer ion structures are   comprised of a helix-turn-coil configuration and a helix-extended   coil region. Elongated dimer species are comprised of   partially-helical monomers arranged in an antiparallel geometry.   This stacked helical bundle may represent the earliest stages of   Nt17-driven oligomer formation. Nt17 monomers and multimers have   been further probed using diethylpyrocarbonate (DEPC). An   N-terminal site (N-terminus of Threonine-3) and Lysine-6 are   modified at higher DEPC concentrations, which led to the   formation of an intermediate monomer structure. These   modifications resulted in decreased extended monomer ion   conformers, as well as a reduction in multimer formation. From   the MDS experiments for the dimer ions, Lys6 residues in both   monomer constituents interact with Ser16 and Glu12 residues on   adjacent peptides; therefore, the decrease in multimer formation   could result from disruption of these or similar interactions.   This work provides a structurally selective model from which to   study Nt17 self-association and provides critical insight toward   Nt17 multimerization and possibly, the early stages of huntingtin   exon 1 aggregation.

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/acs.biochem.5b00478