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Structural properties of target binding by profilaggrin A and B domains and other S100 fused-type calcium-binding proteins

      Highlights

      • S100 fused-type proteins have distinct surface chemistries at target binding site
      • Inter-EF-hand linker residues help S100 fused-type proteins anchor substrate
      • Profilaggrin B domain works with A domain to bind and stabilize protein targets
      • Profilaggrin AB complex binds coiled-coil region of keratin intermediate filaments
      • Annexin 2 domains I and II are positioned to interact with profilaggrin B domain

      Abstract

      Background

      Profilaggrin belongs to the S100 fused-type protein family expressed in keratinocytes and is important for skin barrier integrity. Its N-terminus contains an S100 (“A”) domain and a unique “B” domain with a nuclear localization sequence.

      Objective

      To determine whether profilaggrin B domain cooperates with the S100 domain to bind macromolecules. To characterize the biochemical and structural properties of the profilaggrin N-terminal “AB” domain and compare it to other S100 fused-type proteins.

      Methods

      We used biochemical (protease protection, light scattering, fluorescence spectroscopy, pull-down assays) and computational techniques (sequence analysis, molecular modeling with crystallographic structures) to examine human profilaggrin and S100 fused-type proteins.

      Results

      Comparing profilaggrin S100 crystal structure with models of the other S100 fused-type proteins demonstrated each has a unique chemical composition of solvent accessible surface around the hydrophobic binding pocket. S100 fused-type proteins exhibit higher pocket hydrophobicity than soluble S100 proteins. The inter-EF-hand linker in S100 fused-type proteins contains conserved hydrophobic residues involved in binding substrates. Profilaggrin B domain cooperates with the S100 domain to bind annexin II and keratin intermediate filaments in a calcium-dependent manner using exposed cationic surface. Using molecular modeling we demonstrate profilaggrin B domain likely interacts with annexin II domains I and II. Steric clash analysis shows annexin II N-terminal peptide is favored to bind profilaggrin among S100 fused-type proteins.

      Conclusion

      The N-terminal S100 and B domains of profilaggrin cooperate to bind substrate molecules in granular layer keratinocytes to provide epidermal barrier functions.

      Keywords

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