6xm2

From Proteopedia

The structure of the 4A11.v7 antibody in complex with human TGFb2

Structural highlights

6xm2 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.91Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TGFB2_HUMAN Note=A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9. Defects in TGFB2 are the cause of Loeys-Dietz syndrome 4 (LDS4) [MIM:614816. An aortic aneurysm syndrome with widespread systemic involvement. LDS4 is characterized by arterial tortuosity, aortic dissection, intracranial aneurysm and subarachnoid hemorrhage, hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arachnodactyly, scoliosis, foot deformities, dural ectasia, joint hyperflexibility, and thin skin with easy bruising and striae.^[1]

Function

TGFB2_HUMAN TGF-beta 2 has suppressive effects on interleukin-2 dependent T-cell growth.

Publication Abstract from PubMed

Transforming growth factor-beta (TGFbeta) is a key driver of fibrogenesis. Three TGFbeta isoforms (TGFbeta1, TGFbeta2, and TGFbeta3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFbeta2 and TGFbeta3 have not been well characterized. Here, we show that the latent forms of TGFbeta2 and TGFbeta3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFbeta1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFbeta2 and TGFbeta3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFbeta isoform-selective antibodies demonstrated that TGFbeta2 and TGFbeta3 are independently involved in mouse fibrosis models in vivo, and selective TGFbeta2 and TGFbeta3 inhibition does not lead to the increased inflammation observed with pan-TGFbeta isoform inhibition. A cocrystal structure of a TGFbeta2-anti-TGFbeta2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFbeta2 and/or TGFbeta3 while sparing TGFbeta1 may alleviate fibrosis without toxicity concerns associated with pan-TGFbeta blockade.

TGFbeta2 and TGFbeta3 isoforms drive fibrotic disease pathogenesis.,Sun T, Huang Z, Liang WC, Yin J, Lin WY, Wu J, Vernes JM, Lutman J, Caplazi P, Jeet S, Wong T, Wong M, DePianto DJ, Morshead KB, Sun KH, Modrusan Z, Vander Heiden JA, Abbas AR, Zhang H, Xu M, N'Diaye EN, Roose-Girma M, Wolters PJ, Yadav R, Sukumaran S, Ghilardi N, Corpuz R, Emson C, Meng YG, Ramalingam TR, Lupardus P, Brightbill HD, Seshasayee D, Wu Y, Arron JR Sci Transl Med. 2021 Aug 4;13(605):eabe0407. doi: 10.1126/scitranslmed.abe0407. PMID:34349032^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012 Jul 8;44(8):922-7. doi: 10.1038/ng.2349. PMID:22772368 doi:10.1038/ng.2349
↑ Sun T, Huang Z, Liang WC, Yin J, Lin WY, Wu J, Vernes JM, Lutman J, Caplazi P, Jeet S, Wong T, Wong M, DePianto DJ, Morshead KB, Sun KH, Modrusan Z, Vander Heiden JA, Abbas AR, Zhang H, Xu M, N'Diaye EN, Roose-Girma M, Wolters PJ, Yadav R, Sukumaran S, Ghilardi N, Corpuz R, Emson C, Meng YG, Ramalingam TR, Lupardus P, Brightbill HD, Seshasayee D, Wu Y, Arron JR. TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis. Sci Transl Med. 2021 Aug 4;13(605):eabe0407. PMID:34349032 doi:10.1126/scitranslmed.abe0407