Heparin-mediated dimerization of follistatin.

Experimental Biology and Medicine
Ryan G WalkerThomas B Thompson

Abstract

Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths >dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that hepar...Continue Reading

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Methods Mentioned

BETA
surface plasmon resonance
X-ray
electrophoresis
size exclusion chromatography
size fractionation
chip
chips

Software Mentioned

SymmDock
SIBYLS
BIAevaluation
FoXS
Prism GraphPad
MODELLER
AllosMod
Sedfit
GraphPad Prism
Scrubber

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