title: GARP regulates the bioavailability and activation of TGFβ.
abstract: Glycoprotein-A repetitions predominant protein (GARP) associates with latent transforming growth factor-β (proTGFβ) on the surface of T regulatory cells and platelets; however, whether GARP functions in latent TGFβ activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFβ1 prodomain and that GARP with C192A and C331A mutations can also noncovalently associate with proTGFβ1. Noncovalent association is sufficiently strong for GARP to outcompete latent TGFβ-binding protein for binding to proTGFβ1. Association between GARP and proTGFβ1 prevents the secretion of TGFβ1. Integrin α(V)β(6) and to a lesser extent α(V)β(8) are able to activate TGFβ from the GARP-proTGFβ1 complex. Activation requires the RGD motif of latent TGFβ, disulfide linkage between GARP and latent TGFβ, and membrane association of GARP. Our results show that GARP is a latent TGFβ-binding protein that functions in regulating the bioavailability and activation of TGFβ.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Immune Disease Institute and Children's Hospital, Boston, MA 02115, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Jianghai
authors.initials: J
authors.lastname: Zhu
authors.forename: Xianchi
authors.initials: X
authors.lastname: Dong
authors.forename: Minlong
authors.initials: M
authors.lastname: Shi
authors.forename: Chafen
authors.initials: C
authors.lastname: Lu
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C087215:LRRC32 protein, human; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1