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@ARTICLE{Pazicky:483482,
      author       = {Pazicky, Samuel and Werle, Anna-Leoni A. and Lei, Jian and
                      Loew, Christian and Weininger, Ulrich},
      title        = {{I}mpact of distant peptide substrate residues on enzymatic
                      activity of {S}ly{D}},
      journal      = {Cellular and molecular life sciences},
      volume       = {79},
      number       = {3},
      issn         = {0014-4754},
      address      = {Cham (ZG)},
      publisher    = {Springer International Publishing AG},
      reportid     = {PUBDB-2022-05338},
      pages        = {138},
      year         = {2022},
      abstract     = {Peptidyl-prolyl isomerases (PPIases) catalyze intrinsically
                      slow and often rate-limiting isomerization of prolyl-peptide
                      bonds in unfolded or partially folded proteins, thereby
                      speeding up the folding process and preventing misfolding.
                      They often possess binding and chaperone domains in addition
                      to the domain carrying the isomerization activity. Although
                      generally, their substrates display no identity in their
                      amino acid sequence upstream and downstream of the proline
                      with 20 possibilities for each residue, PPIases are
                      efficient enzymes. SlyD is a highly efficient PPIase
                      consisting of an isomerase domain and an additional
                      chaperone domain. The binding of peptide substrates to SlyD
                      and its enzymatic activity depend to some extend on the
                      proline-proximal residues, however, the impact of
                      proline-distant residues has not been investigated so far.
                      Here, we introduce a label-free NMR-based method to measure
                      SlyD activity on different peptide substrates and analysed
                      the data in the context of obtained binding affinities and
                      several co-crystal structures. We show that especially
                      charged and aromatic residues up to eight positions
                      downstream and three positions upstream of the proline and
                      outside the canonical region of similar conformations affect
                      the activity and binding, although they rarely display
                      distinct conformations in our crystal structures. We
                      hypothesize that these positions primarily influence the
                      association reaction. In the absence of the chaperone domain
                      the isomerase activity strongly correlates with substrate
                      affinity, whereas additional factors play a role in its
                      presence. The mutual orientation of isomerase and chaperone
                      domains depends on the presence of substrates in both
                      binding sites, implying allosteric regulation of enzymatic
                      activity.},
      cin          = {EMBL / CSSB-EMBL / EMBL-User / CSSB-EMBL-CL},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-20120731 / I:(DE-H253)CSSB-EMBL-20141216 /
                      I:(DE-H253)EMBL-User-20120814 /
                      I:(DE-H253)CSSB-EMBL-CL-20210806},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P13-20150101 / EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35184231},
      UT           = {WOS:000757934900001},
      doi          = {10.1007/s00018-022-04179-4},
      url          = {https://bib-pubdb1.desy.de/record/483482},
}