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. 2015 Nov 4;11(11):837. doi: 10.15252/msb.20156269

Figure 1. Structural classification of MAPK‐docking motifs.

Figure 1

  1. The MAPK‐docking groove comprises two distinct regions: the common docking (CD) and the hydrophobic region. These are colored in blue and light brown, respectively, and are shown on the JNK1 surface from the JNK1‐NFAT4 protein–peptide complex crystal structure (Garai et al, 2012). (The CD groove is extended by the ED region, extra negatively charged residues for ERK and p38; see (C); Tanoue et al, 2001.)
  2. Different binding modes of D‐motifs. The hydrophobic docking groove binds three hydrophobic amino acids in a row, while admitting two different spacing schemes. At the same time, θ to φ linker length determines the MAPK specificity of a given motif. These two features can combine freely with each other, resulting in the four basic arrangements shown here.
  3. Distinct binding conformations at the CD groove. N‐termini of longer D‐motifs are variable and ERK2‐ or p38α‐binding peptides may take a variety of conformations—ranging from fully linear (e.g., MEF2A, green) to highly alpha‐helical (e.g., HePTP, magenta).
  4. Structural heterogeneity of D‐motifs. The combinations of the three variable features yield structurally well‐defined, distinct classes of D‐motifs. Many of these models also define separate types of linear motifs, but their consensus sequences are not always exclusive. JNK kinases only admit two major types of motifs, the NFAT4 class (1‐spacing, short linker) and the JIP1 class (2‐spacing, short linker). On the other hand, known ERK1/2 and p38 binder peptides may belong to the greater MEF2A class (1‐spacing, longer linker, linear end), the greater HePTP class (1‐spacing, longer linker, helical end), or the greater DCC class (2‐spacing, longer linker, linear end). A sixth class of ERK or p38 interactors is theoretically also possible (2‐spacing, longer linker, helical end), but this combination can only be observed in long reverse (revD) motifs (Garai et al, 2012), and no classical motif of this type is known up to date. Subtypes and other variants within a given greater class are also featured wherever applicable. These are shown based on structures of MAPK‐docking motif complexes. Dashed lines indicate N‐terminal peptide regions that are usually not visible in the crystal structures, albeit indispensable for binding. Consensus motif of each subtype is shown below, where φU, φL, φA, and φB letters denote positions that are filled by hydrophobic amino acids—L, A, and B refer to the lower pocket, and pockets A and B, respectively—while the θ positions are positively charged (Arg or Lys) while letter “x” denotes arbitrary amino acids.