7y1r
From Proteopedia
Human L-TGF-beta1 in complex with the anchor protein LRRC33
Structural highlights
Disease[TGFB1_HUMAN] Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300]; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.[1] [2] [3] [4] [5] Function[TGFB1_HUMAN] Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. Publication Abstract from PubMedMyeloid lineage cells present the latent form of transforming growth factor-beta1 (L-TGF-beta1) to the membrane using an anchor protein LRRC33. Integrin alphaVbeta8 activates extracellular L-TGF-beta1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-beta1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-beta1/LRRC33 and integrin alphaVbeta8/L-TGF-beta1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-beta1 but not the -beta2 or -beta3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin alphaVbeta8 and L-TGF-beta1, which shows higher avidity and more efficient L-TGF-beta1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit beta8 determines its exquisite affinity to L-TGF-beta1. Together, our findings provide important insights into the specificity of TGF-beta1 signaling achieved by LRRC33 and integrin alphaVbeta8. Specificity of TGF-beta1 signal designated by LRRC33 and integrin alphaVbeta8.,Duan Z, Lin X, Wang L, Zhen Q, Jiang Y, Chen C, Yang J, Lee CH, Qin Y, Li Y, Zhao B, Wang J, Zhang Z Nat Commun. 2022 Aug 25;13(1):4988. doi: 10.1038/s41467-022-32655-9. PMID:36008481[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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