Canonical structural-binding modes in the calmodulin-target protein complexes

Alexandre Denesyuk, Sergei E. Permyakov, Eugene A. Permyakov, Mark Johnson, Konstantin Denessiouk, Vladimir N. Uversky*

*Corresponding author for this work

    Research output: Contribution to journalArticleScientificpeer-review

    2 Citations (Scopus)
    27 Downloads (Pure)

    Abstract

    Intracellular calcium sensor protein calmodulin (CaM) belongs to the large EF-hand protein superfamily. CaM shows a unique and not fully understood ability to bind to multiple targets, allows them to participate in a variety of regulatory processes. The protein has two approximately symmetrical globular domains (the N- and C-lobes). Analysis of the CaM-binding sites of target proteins showed that they have two hydrophobic ‘anchor’ amino acids separated by 10 to 17 residues. Consequently, several CaM-binding motifs: {1–10}, {1–11}, {1–13}, {1–14}, {1–16}, {1–17}, differing by the distance between the two anchor residues along the amino acid sequence, have been identified. Despite extensive structural information on the role of target–protein amino acid residues in the formation of complexes with CaM, much less is known about the role of amino acids from CaM contributing to these interactions. In this work, a quantitative analysis of the contact surfaces of CaM and target proteins has been carried out for 35 representative three-dimensional structures. It has been shown that, in addition to the two hydrophobic terminal residues of the target fragment, the interaction also involves residues that are 4 residues earlier in the sequence (binding mode {1–5}). It has also been found that the N- and C-lobes of CaM bind the {1–5} motif located at the ends of the target in a structurally identical manner. Methionine residues at positions 51 (corresponding to 124 in the C-lobe), 71 (144), and 72 (145) of the CaM amino acid sequence are key hydrophobic residues for this interaction. They are located at the N- and C-boundaries of the even EF-hand motifs. The hydrophobic core of CaM (‘Ф-quatrefoil’) consists of 10 amino acids in the N-lobe (and in the C-lobe): Phe 16 (Phe 89), Phe 19 (Phe 92), Ile 27 (Ile 100), Thr 29 (Ala 102), Leu 32 (Leu 105), Ile 52 (Ile 125), Val 55 (Ala 128), Ile 63 (Val 136), Phe 65 (Tyr 138), and Phe 68 (Phe 141) and do not intersect with the target-binding methionine residues. CaM belongs to the ‘dynamic’ group of EF-hand proteins, in which calcium and protein ligand binding causes only global conformational changes but does not alter the conservative ‘black’ and ‘grey’ clusters described in our earlier works (PLoS One. 2014; 9(10):e109287). The membership of CaM in the ‘dynamic’ group is determined by the triggering and protective methionine layer: Met 51 (Met 124), Met 71 (Met 144) and Met 72 (Met 145). HIGHLIGHTS Interchain interactions in the unique 35 CaM complex structures were analyzed. Methionine amino acids of the N- and C-lobes of CaM form triggering and protective layers. Interactions of the target terminal residues with these methionine layers are structurally identical. CaM belonging to the ‘dynamic’ group is determined by the triggering and protective methionine layer. Communicated by Ramaswamy H. Sarma.

    Original languageEnglish
    Pages (from-to)7582-7594
    Number of pages13
    JournalJournal of Biomolecular Structure and Dynamics
    Volume41
    Issue number16
    DOIs
    Publication statusPublished - 2023
    MoE publication typeA1 Journal article-refereed

    Keywords

    • Calcium; EF-hand; calmodulin–target complex; structural motif; Ф-quatrefoil; ‘black’ and ‘grey’ clusters.

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