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Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus.

Hu L, Ramani S, Czako R, Sankaran B, Yu Y, Smith DF, Cummings RD, Estes MK, Venkataram Prasad BV - Nat Commun (2015)

Bottom Line: Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4.Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart.Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.

View Article: PubMed Central - PubMed

Affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

ABSTRACT
Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart. Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.

No MeSH data available.


Related in: MedlinePlus

Crystal structure of P[11] bovine RV (BRV) VP8*.(a) Sequence alignment of P[11] VP8*s of various representative P[11] human RV (HRV) and BRV strains. The consensus amino acids are coloured using Clustal protein colour scheme in Jalview50. The black * indicates the residues recognizing both LNnT and LNT, and the red * indicates those only bind LNT in P[11] HRV N155. The key amino acid changes between HRV and BRV strains are marked by black boxes. (b) Structural overlay of the structure of P[11] HRV N155 VP8* coloured in grey with that of the P[11] BRV B223 VP8* in pink. The significant structural variations of the J-K loops are indicated by a black box. (c) The J-K loop of P[11] HRV VP8* shows the hydrogen bond interactions between the amino acids leading the loop projecting the strand H. (d) The J-K loop of P[11] BRV VP8* presented in the same orientation and scale as in c. All the residues present in the J-K loop are shown as stick model.
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f5: Crystal structure of P[11] bovine RV (BRV) VP8*.(a) Sequence alignment of P[11] VP8*s of various representative P[11] human RV (HRV) and BRV strains. The consensus amino acids are coloured using Clustal protein colour scheme in Jalview50. The black * indicates the residues recognizing both LNnT and LNT, and the red * indicates those only bind LNT in P[11] HRV N155. The key amino acid changes between HRV and BRV strains are marked by black boxes. (b) Structural overlay of the structure of P[11] HRV N155 VP8* coloured in grey with that of the P[11] BRV B223 VP8* in pink. The significant structural variations of the J-K loops are indicated by a black box. (c) The J-K loop of P[11] HRV VP8* shows the hydrogen bond interactions between the amino acids leading the loop projecting the strand H. (d) The J-K loop of P[11] BRV VP8* presented in the same orientation and scale as in c. All the residues present in the J-K loop are shown as stick model.

Mentions: Despite belonging to the same genotype, the human and bovine P[11] VP8* show differences in their glycan specificity. Although P[11] HRV recognizes the Galβ-GlcNAc motif of either β1,3 or β1,4 linkage, P[11] BRV binds only to the β1,4 motif. Sequence comparison of human and bovine P[11] VP8*s shows 86% amino-acid identity. The residues interacting with the type II glycan in the P[11] HRV VP8* are conserved in the BRV VP8*, indicating that the bovine VP8* can also bind glycans with the β1,4 motif using the same binding site (Fig. 5a). However, there are several significant amino acid changes from human to bovine P[11], including S180A, Y183Q, I158N and F192S. To investigate whether the sequence variations within the VP8*s of the same genotype lead to any structural changes, and how they account for differential glycan binding, we determined the crystal structure of VP8* from a P[11] BRV strain B223 at 2.2 Å resolution (Fig. 5b). Comparison of the human and bovine P[11] VP8* structures shows that despite the overall structural similarity (RMSD=0.66 Å, Fig. 5b), the J-K loop in the bovine VP8*, which has several sequence alterations as noted above, undergoes significant structural change. In the bovine VP8*, this loop with a different set of inter-residue hydrogen bonds projects in an opposite direction compared with that of the human VP8* (Figs 5c,d). The backbone conformational angles in this loop from residues G179 to G184 are also significantly altered.


Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus.

Hu L, Ramani S, Czako R, Sankaran B, Yu Y, Smith DF, Cummings RD, Estes MK, Venkataram Prasad BV - Nat Commun (2015)

Crystal structure of P[11] bovine RV (BRV) VP8*.(a) Sequence alignment of P[11] VP8*s of various representative P[11] human RV (HRV) and BRV strains. The consensus amino acids are coloured using Clustal protein colour scheme in Jalview50. The black * indicates the residues recognizing both LNnT and LNT, and the red * indicates those only bind LNT in P[11] HRV N155. The key amino acid changes between HRV and BRV strains are marked by black boxes. (b) Structural overlay of the structure of P[11] HRV N155 VP8* coloured in grey with that of the P[11] BRV B223 VP8* in pink. The significant structural variations of the J-K loops are indicated by a black box. (c) The J-K loop of P[11] HRV VP8* shows the hydrogen bond interactions between the amino acids leading the loop projecting the strand H. (d) The J-K loop of P[11] BRV VP8* presented in the same orientation and scale as in c. All the residues present in the J-K loop are shown as stick model.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589887&req=5

f5: Crystal structure of P[11] bovine RV (BRV) VP8*.(a) Sequence alignment of P[11] VP8*s of various representative P[11] human RV (HRV) and BRV strains. The consensus amino acids are coloured using Clustal protein colour scheme in Jalview50. The black * indicates the residues recognizing both LNnT and LNT, and the red * indicates those only bind LNT in P[11] HRV N155. The key amino acid changes between HRV and BRV strains are marked by black boxes. (b) Structural overlay of the structure of P[11] HRV N155 VP8* coloured in grey with that of the P[11] BRV B223 VP8* in pink. The significant structural variations of the J-K loops are indicated by a black box. (c) The J-K loop of P[11] HRV VP8* shows the hydrogen bond interactions between the amino acids leading the loop projecting the strand H. (d) The J-K loop of P[11] BRV VP8* presented in the same orientation and scale as in c. All the residues present in the J-K loop are shown as stick model.
Mentions: Despite belonging to the same genotype, the human and bovine P[11] VP8* show differences in their glycan specificity. Although P[11] HRV recognizes the Galβ-GlcNAc motif of either β1,3 or β1,4 linkage, P[11] BRV binds only to the β1,4 motif. Sequence comparison of human and bovine P[11] VP8*s shows 86% amino-acid identity. The residues interacting with the type II glycan in the P[11] HRV VP8* are conserved in the BRV VP8*, indicating that the bovine VP8* can also bind glycans with the β1,4 motif using the same binding site (Fig. 5a). However, there are several significant amino acid changes from human to bovine P[11], including S180A, Y183Q, I158N and F192S. To investigate whether the sequence variations within the VP8*s of the same genotype lead to any structural changes, and how they account for differential glycan binding, we determined the crystal structure of VP8* from a P[11] BRV strain B223 at 2.2 Å resolution (Fig. 5b). Comparison of the human and bovine P[11] VP8* structures shows that despite the overall structural similarity (RMSD=0.66 Å, Fig. 5b), the J-K loop in the bovine VP8*, which has several sequence alterations as noted above, undergoes significant structural change. In the bovine VP8*, this loop with a different set of inter-residue hydrogen bonds projects in an opposite direction compared with that of the human VP8* (Figs 5c,d). The backbone conformational angles in this loop from residues G179 to G184 are also significantly altered.

Bottom Line: Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4.Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart.Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.

View Article: PubMed Central - PubMed

Affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

ABSTRACT
Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart. Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.

No MeSH data available.


Related in: MedlinePlus