title: Latent TGF-β structure and activation.
abstract: Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.
authors.affiliation: Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Minlong
authors.initials: M
authors.lastname: Shi
authors.forename: Jianghai
authors.initials: J
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Lizhi
authors.initials: L
authors.lastname: Mi
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D028341:Activins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D003966:Camurati-Engelmann Syndrome / Q000235:genetics; D002460:Cell Line; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D053779:Latent TGF-beta Binding Proteins; D009842:Oligopeptides; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C422405:activin A; C073878:integrin alphavbeta6; D028341:Activins; C047981:arginyl-glycyl-aspartic acid