TGF-β Superfamily Ligands Structure


Mature and active TGF-β ligands are formed by much larger precursor molecules. The active precursors include two of the carboxy-terminal mature domains in either homo- or heterodimer conformations. The amino-terminal signal peptide is cleaved at a conserved Arg-X-Arg-Arg site when translocated into the lumen of the rough endoplasmic reticulum, leaving the carboxy-terminal TGF-β superfamily mature monomer polypeptide. For TGF-β superfamily members, the mature domain is related to a latency associated peptide (LAP) which helps the protein move toward sites of activation or storage.

The critical difference to distinguish the subfamilies is the number and location of the cysteines, whose spacing and conservation are the hallmark of the TGF-β family members. The three TGF-β isoforms contain nine cysteines. Four cysteine pairs with each other intramolecularly and the other five cysteine forms a disulfide bridge with a nearby monomer which leads a dimer formation. All other TGF-β superfamily members contain seven or five cysteines. For seven cysteines TGF-β molecules, they share a common pattern. Six cysteines form a “cystine knot” which holds each monomer subunit together. The fourth cysteine in each monomer forms Disulfide Bridge in a covalently linked with an adjacent monomer. Many of these seven cysteine-containing ligands are classified into bone morphogenetic proteins (BMPs) or growth differentiation factors (GDFs). The five cysteines TGF beta molecules are Lefty A, Lefty B, BMP-15, GDF-3 and GDF-9. These ligands are biologically active in non-covalent dimers formation.

 

Related literatures

1. Derynck R, Miyazono K. 2 TGF-β and the TGF-β Family[J]. Cold Spring Harbor Monograph Archive, 2008, 50: 29-43.

2. Daopin S, Piez K A, Ogawa Y, et al. Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily[J]. Science, 1992, 257(5068): 369-373.

3. Mittl P R, Priestle J P, Cox D A, et al. The crystal structure of TGF-beta 3 and comparison to TGF-beta 2: implications for receptor binding[J]. Protein science: a publication of the Protein Society, 1996, 5(7): 1261.

 

BMP Modulator
GDNF Family Signaling Molecules
TGF-beta Family Modulators

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