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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.


Key FSH/FSHR interface salt bridges underlying the electrostatic distinctions between FSH15(TAG) and FSH24(TAG).FSH is depicted as cyan ribbons with key residues shown as green/CPK-colored sticks, whereas FSHR is rendered via yellow ribbons and yellow/CPK-colored sticks.
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pone.0137897.g011: Key FSH/FSHR interface salt bridges underlying the electrostatic distinctions between FSH15(TAG) and FSH24(TAG).FSH is depicted as cyan ribbons with key residues shown as green/CPK-colored sticks, whereas FSHR is rendered via yellow ribbons and yellow/CPK-colored sticks.

Mentions: Conformational strain within protein molecules is somewhat difficult to unambiguously characterize because it is frequently distributed across the molecule and can vary substantially in a dynamic fashion. The inter-monomer electrostatic coupling can be more readily interpreted, however. A key component of the FSH/FSHR interaction is mediated by a series of fairly strong salt bridges (two binding FSHα to FSHR and two between FSHβ and FSHR). These four key examples are depicted in Fig 11. As summarized in Table 2, the capacity of an FSH/FSHR complex to sustain each of these salt bridges varies significantly as a function of glycosylation state. In comparing fully deglycosylated FSH with FSH15(TAG) and FSH24(TAG) we find one salt bridge (emanating from Asp93 on FSHβ) to retain nearly invariant strength and persistence regardless of FSH glycosylation state, but the other three exhibit tangible variation. The coupling between Lys51 on FSHα and Asp153 on FSHR is modestly weaker and less persistent for FSH15(TAG) than is the case for FSH24(TAG), but more substantial salt bridge disruption is evident for FSH24(TAG), with significantly weaker and less persistent bonds originating from Lys91 on FSHα and from Lys40 on FSHβ.


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)

Key FSH/FSHR interface salt bridges underlying the electrostatic distinctions between FSH15(TAG) and FSH24(TAG).FSH is depicted as cyan ribbons with key residues shown as green/CPK-colored sticks, whereas FSHR is rendered via yellow ribbons and yellow/CPK-colored sticks.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137897.g011: Key FSH/FSHR interface salt bridges underlying the electrostatic distinctions between FSH15(TAG) and FSH24(TAG).FSH is depicted as cyan ribbons with key residues shown as green/CPK-colored sticks, whereas FSHR is rendered via yellow ribbons and yellow/CPK-colored sticks.
Mentions: Conformational strain within protein molecules is somewhat difficult to unambiguously characterize because it is frequently distributed across the molecule and can vary substantially in a dynamic fashion. The inter-monomer electrostatic coupling can be more readily interpreted, however. A key component of the FSH/FSHR interaction is mediated by a series of fairly strong salt bridges (two binding FSHα to FSHR and two between FSHβ and FSHR). These four key examples are depicted in Fig 11. As summarized in Table 2, the capacity of an FSH/FSHR complex to sustain each of these salt bridges varies significantly as a function of glycosylation state. In comparing fully deglycosylated FSH with FSH15(TAG) and FSH24(TAG) we find one salt bridge (emanating from Asp93 on FSHβ) to retain nearly invariant strength and persistence regardless of FSH glycosylation state, but the other three exhibit tangible variation. The coupling between Lys51 on FSHα and Asp153 on FSHR is modestly weaker and less persistent for FSH15(TAG) than is the case for FSH24(TAG), but more substantial salt bridge disruption is evident for FSH24(TAG), with significantly weaker and less persistent bonds originating from Lys91 on FSHα and from Lys40 on FSHβ.

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.