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Glycosylation Effects on FSH-FSHR Interaction Dynamics: A Case Study of Different FSH Glycoforms by Molecular Dynamics Simulations.

Meher BR, Dixit A, Bousfield GR, Lushington GH - PLoS ONE (2015)

Bottom Line: However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan.Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile.FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas, United States of America.

ABSTRACT
The gonadotropin known as follicle-stimulating hormone (FSH) plays a key role in regulating reproductive processes. Physiologically active FSH is a glycoprotein that can accommodate glycans on up to four asparagine residues, including two sites in the FSHα subunit that are critical for biochemical function, plus two sites in the β subunit, whose differential glycosylation states appear to correspond to physiologically distinct functions. Some degree of FSHβ hypo-glycosylation seems to confer advantages toward reproductive fertility of child-bearing females. In order to identify possible mechanistic underpinnings for this physiological difference we have pursued computationally intensive molecular dynamics simulations on complexes between the high affinity site of the gonadal FSH receptor (FSHR) and several FSH glycoforms including fully-glycosylated (FSH24), hypo-glycosylated (e.g., FSH15), and completely deglycosylated FSH (dgFSH). These simulations suggest that deviations in FSH/FSHR binding profile as a function of glycosylation state are modest when FSH is adorned with only small glycans, such as single N-acetylglucosamine residues. However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan. Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile. FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

No MeSH data available.


(a) Plot showing RMSF values of Cα atoms from MD simulations of free/unbound FSH and FSHr-bound models of FSH. RMSF changes were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128-Ala131. Residues with RMSF changes of at least >2.0 Å are labeled inside the bars in each subunit. (b) Difference of RMSF values for FSHR-bound FSH and free-FSH models. The residues with absolute difference larger than 1.0 Å are labeled by one cutoff dashed black line.
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pone.0137897.g009: (a) Plot showing RMSF values of Cα atoms from MD simulations of free/unbound FSH and FSHr-bound models of FSH. RMSF changes were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128-Ala131. Residues with RMSF changes of at least >2.0 Å are labeled inside the bars in each subunit. (b) Difference of RMSF values for FSHR-bound FSH and free-FSH models. The residues with absolute difference larger than 1.0 Å are labeled by one cutoff dashed black line.

Mentions: Fig 9a compares RMSF values for free and FSHR-bound models of FSH and Fig 9b compare the difference between the RMSFs of free and FSH-bound models. Significant reductions in RMSF were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128—Ala131. Reduced flexibility was noted for the region centered on αMet69 and a significant reduction in flexibility was associated with βLys128—Ala131. Both regions were located in the same region in FSH that formed the sulfo-Tyr335 binding pocket. Met45 was located in at the other end of the FSH molecule in αL2, which engages the receptor. Flexibility in two regions near the amino terminus of FSHα and in the C-terminal end of FSHβ was unaffected by binding to the FSHR.


Glycosylation Effects on FSH-FSHR Interaction Dynamics: A Case Study of Different FSH Glycoforms by Molecular Dynamics Simulations.

Meher BR, Dixit A, Bousfield GR, Lushington GH - PLoS ONE (2015)

(a) Plot showing RMSF values of Cα atoms from MD simulations of free/unbound FSH and FSHr-bound models of FSH. RMSF changes were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128-Ala131. Residues with RMSF changes of at least >2.0 Å are labeled inside the bars in each subunit. (b) Difference of RMSF values for FSHR-bound FSH and free-FSH models. The residues with absolute difference larger than 1.0 Å are labeled by one cutoff dashed black line.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581761&req=5

pone.0137897.g009: (a) Plot showing RMSF values of Cα atoms from MD simulations of free/unbound FSH and FSHr-bound models of FSH. RMSF changes were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128-Ala131. Residues with RMSF changes of at least >2.0 Å are labeled inside the bars in each subunit. (b) Difference of RMSF values for FSHR-bound FSH and free-FSH models. The residues with absolute difference larger than 1.0 Å are labeled by one cutoff dashed black line.
Mentions: Fig 9a compares RMSF values for free and FSHR-bound models of FSH and Fig 9b compare the difference between the RMSFs of free and FSH-bound models. Significant reductions in RMSF were noted in two regions in the FSHα subunit centered on residues Met45 and Met69 and one region in the FSHβ subunit centered on residues Lys128—Ala131. Reduced flexibility was noted for the region centered on αMet69 and a significant reduction in flexibility was associated with βLys128—Ala131. Both regions were located in the same region in FSH that formed the sulfo-Tyr335 binding pocket. Met45 was located in at the other end of the FSH molecule in αL2, which engages the receptor. Flexibility in two regions near the amino terminus of FSHα and in the C-terminal end of FSHβ was unaffected by binding to the FSHR.

Bottom Line: However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan.Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile.FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas, United States of America.

ABSTRACT
The gonadotropin known as follicle-stimulating hormone (FSH) plays a key role in regulating reproductive processes. Physiologically active FSH is a glycoprotein that can accommodate glycans on up to four asparagine residues, including two sites in the FSHα subunit that are critical for biochemical function, plus two sites in the β subunit, whose differential glycosylation states appear to correspond to physiologically distinct functions. Some degree of FSHβ hypo-glycosylation seems to confer advantages toward reproductive fertility of child-bearing females. In order to identify possible mechanistic underpinnings for this physiological difference we have pursued computationally intensive molecular dynamics simulations on complexes between the high affinity site of the gonadal FSH receptor (FSHR) and several FSH glycoforms including fully-glycosylated (FSH24), hypo-glycosylated (e.g., FSH15), and completely deglycosylated FSH (dgFSH). These simulations suggest that deviations in FSH/FSHR binding profile as a function of glycosylation state are modest when FSH is adorned with only small glycans, such as single N-acetylglucosamine residues. However, substantial qualitative differences emerge between FSH15 and FSH24 when FSH is decorated with a much larger, tetra-antennary glycan. Specifically, the FSHR complex with hypo-glycosylated FSH15 is observed to undergo a significant conformational shift after 5-10 ns of simulation, indicating that FSH15 has greater conformational flexibility than FSH24 which may explain the more favorable FSH15 kinetic profile. FSH15 also exhibits a stronger binding free energy, due in large part to formation of closer and more persistent salt-bridges with FSHR.

No MeSH data available.