Artikel ; Online: Differential glycosylation in mutant vitamin D-binding protein decimates the binding stability of vitamin D.
Journal of biomolecular structure & dynamics
2023 Band 42, Heft 10, Seite(n) 5365–5375
Abstract: Vitamin D (VD) is produced by the skin upon exposure to sunlight or is obtained from dietary sources. Several risk factors are associated with VD deficiency including mutations and post-translational modifications in its transport protein known as ... ...
Abstract | Vitamin D (VD) is produced by the skin upon exposure to sunlight or is obtained from dietary sources. Several risk factors are associated with VD deficiency including mutations and post-translational modifications in its transport protein known as vitamin D binding protein (VDBP) or GC-globulin. The two common single nucleotide polymorphisms rs7041 and rs4588 create three major isoforms of VDBP, including GC-1F also called wild type, GC1S, and GC-2. The 3D models for both GC-1F and GC-2 were constructed in their glycosylated states to decipher the effect of these mutations on the overall conformational changes and VD-binding affinity. The binding affinities were estimated using the Molecular Mechanics Poison-Boltzmann surface area (MM-PBSA) method and conformational changes were investigated after free energy landscapes estimations. Total free energies suggest that GC-1F exhibits stronger affinity (ΔE = -116.09 kJ/mol) than GC-2 (ΔE = -95 kJ/mol) variant with VD. The GC-1F isoforms had more streamlined motion compared to GC-2 isoforms, predicting a trade-off between cross-talk residues that significantly impacts protein structural stability. The data suggest that glycation at Thr418 plays a vital role in the overall VDBP-VD affinity by stabilizing the N-T loop that holds the domain I (VD-pocket) and domain III intact. The loss of glycation in GC-2 has a pivotal role in the inter-domain conformational stability of VDBP, which may ultimately affect VD transportation and maturation. These findings describe a novel mechanism in how mutations distant from the VD-active site change the overall conformational of the VDBP and abrogate the VDBP-VD interaction.Communicated by Ramaswamy H. Sarma. |
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Mesh-Begriff(e) | Vitamin D-Binding Protein/metabolism ; Vitamin D-Binding Protein/genetics ; Vitamin D-Binding Protein/chemistry ; Glycosylation ; Protein Binding ; Vitamin D/metabolism ; Vitamin D/chemistry ; Humans ; Mutation ; Molecular Dynamics Simulation ; Protein Stability ; Protein Conformation ; Models, Molecular ; Thermodynamics ; Polymorphism, Single Nucleotide ; Binding Sites ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Protein Isoforms/chemistry ; Protein Isoforms/metabolism ; Protein Isoforms/genetics |
Sprache | Englisch |
Erscheinungsdatum | 2023-06-25 |
Erscheinungsland | England |
Dokumenttyp | Journal Article |
ZDB-ID | 49157-3 |
ISSN | 1538-0254 ; 0739-1102 |
ISSN (online) | 1538-0254 |
ISSN | 0739-1102 |
DOI | 10.1080/07391102.2023.2226742 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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