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Activin A binds to perlecan through its pro-region that has heparin/heparan sulfate binding activity.


ABSTRACT: Activin A, a member of the transforming growth factor-? family, plays important roles in hormonal homeostasis and embryogenesis. In this study, we produced recombinant human activin A and examined its abilities to bind to extracellular matrix proteins. Recombinant activin A expressed in 293-F cells was purified as complexes of mature dimeric activin A with its pro-region. Among a panel of extracellular matrix proteins tested, recombinant activin A bound to perlecan and agrin, but not to laminins, nidogens, collagens I and IV, fibronectin, and nephronectin. The binding of recombinant activin A to perlecan was inhibited by heparin and high concentrations of NaCl and abolished by heparitinase treatment of perlecan, suggesting that activin A binds to the heparan sulfate chains of perlecan. In support of this possibility, recombinant activin A was capable of directly binding to heparin and heparan sulfate chains. Site-directed mutagenesis of recombinant activin A revealed that clusters of basic amino acid residues, Lys(259)-Lys(263) and Lys(270)-Lys(272), in the pro-region were required for binding to perlecan. Interestingly, deletion of the peptide segment Lys(259)-Gly(277) containing both basic amino acid clusters from the pro-region did not impair the activity of activin A to stimulate Smad-dependent gene expressions, although it completely ablated the perlecan-binding activity. The binding of activin A to basement membrane heparan sulfate proteoglycans through the basic residues in the pro-region was further confirmed by in situ activin A overlay assays using frozen tissue sections. Taken together, the present results indicate that activin A binds to heparan sulfate proteoglycans through its pro-region and thereby regulates its localization within tissues.

SUBMITTER: Li S 

PROVIDER: S-EPMC2978593 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Activin A binds to perlecan through its pro-region that has heparin/heparan sulfate binding activity.

Li Shaoliang S   Shimono Chisei C   Norioka Naoko N   Nakano Itsuko I   Okubo Tetsuo T   Yagi Yoshiko Y   Hayashi Maria M   Sato Yuya Y   Fujisaki Hitomi H   Hattori Shunji S   Sugiura Nobuo N   Kimata Koji K   Sekiguchi Kiyotoshi K  

The Journal of biological chemistry 20100915 47


Activin A, a member of the transforming growth factor-β family, plays important roles in hormonal homeostasis and embryogenesis. In this study, we produced recombinant human activin A and examined its abilities to bind to extracellular matrix proteins. Recombinant activin A expressed in 293-F cells was purified as complexes of mature dimeric activin A with its pro-region. Among a panel of extracellular matrix proteins tested, recombinant activin A bound to perlecan and agrin, but not to laminins  ...[more]

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