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@ARTICLE{Gauhar:172156,
      author       = {Gauhar, Aziz and Shaykhalishahi, Hamed and Gremer, Lothar
                      and Mirecka, Ewa and Hoyer, Wolfgang},
      title        = {{I}mpact of subunit linkages in an engineered homodimeric
                      binding protein to α-synuclein},
      journal      = {Protein engineering design and selection},
      volume       = {27},
      number       = {12},
      issn         = {0269-2139},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2014-05666},
      pages        = {473-479},
      year         = {2014},
      abstract     = {Aggregation of the protein α-synuclein (α-syn) has been
                      implicated in Parkinson's disease and other
                      neurodegenerative disorders, collectively referred to as
                      synucleinopathies. The β-wrapin AS69 is a small engineered
                      binding protein to α-syn that stabilizes a β-hairpin
                      conformation of monomeric α-syn and inhibits α-syn
                      aggregation at substoichiometric concentrations. AS69 is a
                      homodimer whose subunits are linked via a disulfide bridge
                      between their single cysteine residues, Cys-28. Here we show
                      that expression of a functional dimer as a single
                      polypeptide chain is achievable by head-to-tail linkage of
                      AS69 subunits. Choice of a suitable linker is essential for
                      construction of head-to-tail dimers that exhibit
                      undiminished α-syn affinity compared with the solely
                      disulfide-linked dimer. We characterize AS69-GS3, a
                      head-to-tail dimer with a glycine-serine-rich linker, under
                      oxidized and reduced conditions in order to evaluate the
                      impact of the Cys28-disulfide bond on structure, stability
                      and α-syn binding. Formation of the disulfide bond causes
                      compaction of AS69-GS3, increases its thermostability, and
                      is a prerequisite for high-affinity binding to α-syn.
                      Comparison of AS69-GS3 and AS69 demonstrates that
                      head-to-tail linkage promotes α-syn binding by affording
                      accelerated disulfide bond formation.},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {453 - Physics of the Cell (POF2-453)},
      pid          = {G:(DE-HGF)POF2-453},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000345837300002},
      doi          = {10.1093/protein/gzu047},
      url          = {https://juser.fz-juelich.de/record/172156},
}