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@ARTICLE{Dorendorf:646263,
      author       = {Dorendorf, Till and Gravenhorst, Peter and Mayans, Olga},
      title        = {{M}olecular identifiers of the evolutionarily conserved
                      titin pseudokinase},
      journal      = {The biochemical journal / Reviews},
      volume       = {483},
      number       = {01},
      issn         = {1470-8728},
      address      = {London [u.a.]},
      publisher    = {Portland Press},
      reportid     = {PUBDB-2026-00786},
      pages        = {55 - 70},
      year         = {2026},
      note         = {ISSN 1470-8728 not unique: **2 hits**.},
      abstract     = {Titin kinase (TK) is an enigmatic pseudokinase specific to
                      the striated muscle of vertebrates. Embedded within the
                      contractile sarcomere and flanked by extensible regulatory
                      tails, TK is thought to act as a mechanoreceptor that senses
                      mechanical signals arising from muscle function. Studies on
                      TK so far have focused narrowly on the human representative,
                      whose phosphotransfer activity remains questioned. To
                      investigate whether the pseudokinase character is a hallmark
                      of TK, we studied sequences of distantly evolved fish
                      representatives and rationalized conservation patterns by
                      solving the crystal structure of TK from medaka (isoform b).
                      We find that sequence deviations in functional motifs
                      involved in ATP and magnesium binding, respectively θxK
                      (θ: bulky hydrophobic residue) and EFG, are evolutionarily
                      conserved in TK. Beyond the kinase domain, N- and C-terminal
                      flanking tails show remarkable structural similarity across
                      orthologues, even though sequence conservation is limited to
                      individual residues and short motifs: a YD-motif in the
                      N-terminal tail; a [R/K]H[R/K]RYY sequence, a R-7x-R motif
                      and position -2 of the latter in the C-terminal tail. Motifs
                      in the C-terminal tail consistently covary with the
                      divergent functional motifs of TK, being part of its
                      pseudokinase signature. Contrary with these general
                      features, the putatively inhibitory interaction of the
                      catalytic aspartate with a tyrosine from loop P+1 is
                      primarily confined to mammals. Finally, based on sequence
                      clustering analysis, we identify TK subgroupings and propose
                      a classification of titin genes from fish into a and b
                      isoforms (ttna and ttnb) that can assist future studies. A
                      curated genomic annotation is provided.},
      cin          = {EMBL-User},
      ddc          = {540},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1042/BCJ20253442},
      url          = {https://bib-pubdb1.desy.de/record/646263},
}