Two Structural Motifs within Canonical EF-Hand Calcium-Binding Domains Identify Five Different Classes of Calcium Buffers and Sensors

Denessiouk, Konstantin; Permyakov, Sergei E.; Denesyuk, Alexander I.; Permyakov, Eugene A.; Johnson, Mark S.

doi:10.1371/journal.pone.0109287

Cited by 55 publications

(59 citation statements)

References 85 publications

(81 reference statements)

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“…CD EFhd2 may belong to type I or IV, because these types have an open conformation in the Ca 2+ -bound form. In the apo state, type I EF-hand domains (Parvalbumin, PVALB) maintain an open conformation; however, type IV EF-hand domains (CaM and Troponin C, TnC) exhibit a closed conformation48. This structural difference between types I and IV raised the possibility that the CD EFhd2 may belong to type I, because we expect CD EFhd2 to have an open conformation in the apo state based on the mutant structures and CSP analysis.…”

Section: Discussionmentioning

confidence: 97%

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Structural implications of Ca2+-dependent actin-bundling function of human EFhd2/Swiprosin-1

Park

Kwon

et al. 2016

Sci Rep

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EFhd2/Swiprosin-1 is a cytoskeletal Ca2+-binding protein implicated in Ca2+-dependent cell spreading and migration in epithelial cells. EFhd2 domain architecture includes an N-terminal disordered region, a PxxP motif, two EF-hands, a ligand mimic helix and a C-terminal coiled-coil domain. We reported previously that EFhd2 displays F-actin bundling activity in the presence of Ca2+ and this activity depends on the coiled-coil domain and direct interaction of the EFhd2 core region. However, the molecular mechanism for the regulation of F-actin binding and bundling by EFhd2 is unknown. Here, the Ca2+-bound crystal structure of the EFhd2 core region is presented and structures of mutants defective for Ca2+-binding are also described. These structures and biochemical analyses reveal that the F-actin bundling activity of EFhd2 depends on the structural rigidity of F-actin binding sites conferred by binding of the EF-hands to Ca2+. In the absence of Ca2+, the EFhd2 core region exhibits local conformational flexibility around the EF-hand domain and C-terminal linker, which retains F-actin binding activity but loses the ability to bundle F-actin. In addition, we establish that dimerisation of EFhd2 via the C-terminal coiled-coil domain, which is necessary for F-actin bundling, occurs through the parallel coiled-coil interaction.

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Section: Discussionmentioning

confidence: 97%

“…Denessiouk et al . classified EF-hand domains in five groups based on differences in the structural changes in the core region (hydrophobic cluster I and II) upon Ca 2+ binding48. CD EFhd2 may belong to type I or IV, because these types have an open conformation in the Ca 2+ -bound form.…”

Section: Discussionmentioning

confidence: 99%

Structural implications of Ca2+-dependent actin-bundling function of human EFhd2/Swiprosin-1

Park

Kwon

et al. 2016

Sci Rep

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“…The two EF-hands are related by a prototypical two-fold pseudo symmetry axis, packing against one another to form a four helix-bundle (Denessiouk et al, 2014; Figure 2A). The loop regions within each EF-hand engage one another through backbone hydrogen bonding to form a two-stranded anti-parallel β-sheet across the pseudo two-fold axis, yielding an EFβ-scaffold as observed in calmodulin (Babu et al, 1988).…”

Section: Resultsmentioning

confidence: 99%

“…An extensive network of conserved aromatic residues dominates the hydrophobic core. While a subset of the aromatic network is conserved across EF-Hand-containing proteins (Denessiouk et al, 2014), the network is surprisingly expanded in ACF7 and may contribute to domain stabilization.…”

Section: Resultsmentioning

confidence: 99%

Structure of the ACF7 EF-Hand-GAR Module and Delineation of Microtubule Binding Determinants

2017

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SUMMARY Spectraplakins are large molecules that cross-link F-actin and microtubules (MTs). Mutations in spectraplakins yield defective cell polarization, aberrant focal adhesion dynamics, and dystonia. We present the 2.8 Å crystal structure of the hACF7 EF1-EF2-GAR MT-binding module and delineate the GAR residues critical for MT binding. The EF1-EF2 and GAR domains are autonomous domains connected by a flexible linker. The EF1-EF2 domain is an EFβ-scaffold with two bound Ca2+ ions that straddles a N-terminal α-helix. The GAR domain has a unique α/β sandwich fold that coordinates Zn2+. While the EF1-EF2 domain is not sufficient for MT-binding, the GAR domain is and likely enhances EF1-EF2-MT engagement. Residues in a conserved basic patch, distal to the GAR domain’s Zn2+ binding site, mediate MT binding.

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“…Although the most conserved residues of these regions mainly provide the side chains directly coordinating the Ca 2? ion, residues F15, L33, and F74 belong to the recently identified highly conserved characteristic clusters (motifs) of interacting residues found in all families of the EF-hand proteins, named 'black' and 'gray' clusters [47]. These motifs provide a supporting scaffold for the DxDxDG Ca 2?…”

Section: Interactions Of Il-11 With Calcium-binding Proteinsmentioning

confidence: 99%

Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

Permyakov

Uversky

Permyakov

2016

Cell Biochem Biophys

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Cytokine interleukin-11 (IL-11) is a multifunctional protein with diverse roles in the normal cell signaling and in various pathologies. The structure of IL-11 is characterized by a four-helix bundle motif comprising two pairs of antiparallel α-helices arranged in an up-up-down-down configuration. Evaluation of the intrinsic disorder predisposition of human IL-11 by several computational tools clearly shows that this protein is predicted to have functional disordered regions potentially involved in interaction with natural binding partners. Signaling by IL-11 proceeds via an interaction of the protein with its membrane-specific receptor IL-11Rα and a subsequent interaction of the complex with the transmembrane signal-transducing receptor GP130. Cytoplasmic domain of IL-11Rα is predicted to be very disordered, and noticeable amount of disorder is present even in the large extracellular domain of the protein. GP130 is also predicted to have long disordered region that is located at the C-terminal of the protein and is expected to have several disorder-based binding sites. It shows that intrinsic disorder might play an important role in functioning of this signaling machine. A specific subset of the calcium sensor proteins (calmodulin, S100P, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants in a range of 1-19 μM, and the structural features of their hinge regions likely ensure selectivity and calcium sensitivity of IL-11 binding to the EF-hand proteins studied. IL-11 exhibits multiple effects on hematopoietic and non-hematopoietic systems. It plays a major role in orchestrating complex processes of tumor development and progression.

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Two Structural Motifs within Canonical EF-Hand Calcium-Binding Domains Identify Five Different Classes of Calcium Buffers and Sensors

Cited by 55 publications

References 85 publications

Structural implications of Ca2+-dependent actin-bundling function of human EFhd2/Swiprosin-1

Structural implications of Ca2+-dependent actin-bundling function of human EFhd2/Swiprosin-1

Structure of the ACF7 EF-Hand-GAR Module and Delineation of Microtubule Binding Determinants

Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

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