Activin-A binds follistatin and type II receptors through overlapping binding sites: generation of mutants with isolated binding activities

Endocrinology
Craig A HarrisonDavid M Robertson

Abstract

Follistatin is a potent extracellular antagonist of members of the TGFbeta superfamily that use activin type II receptors (ActRII/IIB) as part of their signaling complex. A recent crystallographic study indicates that follistatin contacts activin-A residues at both the type I (ALK4) and type II receptor binding interfaces. However, the relative contribution of these two sites on human activin-A to follistatin binding has not been determined. Residues at these sites were mutated to alanine and mutants were screened for their ability to bind follistatin and ActRII and induce FSH secretion from a gonadotrope cell line. Despite extensive mutagenesis across the type I receptor interface, activin-A affinity for follistatin was not significantly diminished. In contrast, mutagenesis of residues at the type II binding interface had pronounced effects on activin's interaction with follistatin. In particular, residues Leu92, Tyr94, Ile100, and Lys102 were critical for high-affinity follistatin binding. Interestingly, mutation of another primary determinant of ActRII/IIB binding, Ser90, did not affect follistatin affinity, suggesting that the interaction surfaces for type II receptors and follistatin were overlapping but not identical. In ...Continue Reading

Citations

May 18, 2012·Molecular Endocrinology·Jennifer N CashThomas B Thompson
Dec 22, 2015·Molecular and Cellular Endocrinology·Katharine E JohnsonCraig A Harrison
Feb 15, 2012·Molecular and Cellular Endocrinology·Louise M BilezikjianWylie W Vale
Jul 19, 2011·Molecular and Cellular Endocrinology·Kelly L WaltonCraig A Harrison
Jan 31, 2014·Journal of Tissue Engineering and Regenerative Medicine·Peter V HauserNorimoto Yanagawa
May 13, 2015·Reproduction : the Official Journal of the Society for the Study of Fertility·Claire GlisterPhil G Knight
Nov 18, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Justin L ChenCraig A Harrison
Sep 16, 2017·Experimental & Molecular Medicine·Hui ZhengXiao Xiao
Jul 14, 2011·Endocrinology·Yogeshwar MakanjiCraig A Harrison
May 13, 2018·The Journal of Pharmacology and Experimental Therapeutics·Chuan ShenAngela W Norton
Jul 23, 2014·Endocrine Reviews·Yogeshwar MakanjiTeresa K Woodruff
Apr 10, 2008·The Journal of Biological Chemistry·Yogeshwar MakanjiCraig A Harrison
Jun 23, 2016·Cold Spring Harbor Perspectives in Biology·Maria Namwanje, Chester W Brown

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