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@ARTICLE{Fluhrer:136438,
      author       = {Fluhrer, Regina and Martin, Lucas and Klier, Bärbel and
                      Haug-Kröper, Martina and Grammer, Gudula and Nuscher,
                      Brigitte and Haass, Christian},
      title        = {{T}he α-helical content of the transmembrane domain of the
                      {B}ritish dementia protein-2 ({B}ri2) determines its
                      processing by signal peptide peptidase-like 2b ({SPPL}2b).},
      journal      = {The journal of biological chemistry},
      volume       = {287},
      number       = {7},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.60645},
      reportid     = {DZNE-2020-02760},
      pages        = {5156-5163},
      year         = {2012},
      abstract     = {Regulated intramembrane proteolysis is a widely accepted
                      concept describing the processing of various transmembrane
                      proteins via ectodomain shedding followed by an
                      intramembrane cleavage. The resulting cleavage products can
                      be involved in reverse signaling. Presenilins, which
                      constitute the active center of the γ-secretase complex,
                      signal peptide peptidase (SPP), and its homologues, the
                      SPP-like (SPPL) proteases are members of the family of
                      intramembrane-cleaving aspartyl proteases of the GXGD-type.
                      We recently demonstrated that Bri2 (itm2b) is a substrate
                      for regulated intramembrane proteolysis by SPPL2a and
                      SPPL2b. Intramembrane cleavage of Bri2 is triggered by an
                      initial shedding event catalyzed by A Disintegrin and
                      Metalloprotease 10 (ADAM10). Additionally primary sequence
                      determinants within the intracellular domain, the
                      transmembrane domain and the luminal juxtamembrane domain
                      are required for efficient cleavage of Bri2 by SPPL2b. Using
                      mutagenesis and circular dichroism spectroscopy we now
                      demonstrate that a high α-helical content of the Bri2
                      transmembrane domain (TMD) reduces cleavage efficiency of
                      Bri2 by SPPL2b, while the presence of a GXXXG dimerization
                      motif influences the intramembrane cleavage only to a minor
                      extent. Surprisingly, only one of the four conserved
                      intramembrane glycine residues significantly affects the
                      secondary structure of the Bri2 TMD and thereby its
                      intramembrane cleavage. Other glycine residues do not
                      influence the α-helical content of the transmembrane domain
                      nor its intramembrane processing.},
      keywords     = {ADAM Proteins: genetics / ADAM Proteins: metabolism /
                      ADAM10 Protein / Amino Acid Motifs / Amyloid Precursor
                      Protein Secretases: genetics / Amyloid Precursor Protein
                      Secretases: metabolism / Aspartic Acid Endopeptidases:
                      genetics / Aspartic Acid Endopeptidases: metabolism /
                      Circular Dichroism: methods / HEK293 Cells / Humans /
                      Membrane Glycoproteins / Membrane Proteins: genetics /
                      Membrane Proteins: metabolism / Mutagenesis / Protein
                      Structure, Tertiary / Proteolysis / ITM2B protein, human
                      (NLM Chemicals) / Membrane Glycoproteins (NLM Chemicals) /
                      Membrane Proteins (NLM Chemicals) / Amyloid Precursor
                      Protein Secretases (NLM Chemicals) / Aspartic Acid
                      Endopeptidases (NLM Chemicals) / SPPL2b protein, human (NLM
                      Chemicals) / ADAM Proteins (NLM Chemicals) / ADAM10 Protein
                      (NLM Chemicals) / ADAM10 protein, human (NLM Chemicals)},
      cin          = {AG Fluhrer / AG Haass old},
      ddc          = {540},
      cid          = {I:(DE-2719)1110000-2 / I:(DE-2719)1110007},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22194595},
      pmc          = {pmc:PMC3281599},
      doi          = {10.1074/jbc.M111.328104},
      url          = {https://pub.dzne.de/record/136438},
}