PROSITE documentation PDOC00223

TGF-beta family signature and profile

Transforming growth factor-β (TGF-β) [1] is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-β-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein. A number of proteins are known to be related to TGF-β-1 [1,2,3]. They are listed below.

• Two other forms of TGF-β have been found, they are known as TGF-β-2 and TGF-β-3.
• Mullerian inhibitory substance (MIS), produced by the testis, which is responsible for the regression of the Mullerian ducts in the male embryo.
• Inhibins, which inhibit the secretion of follitropin by the pituitary gland, and activins which have the reverse action. Inhibins are heterodimer of an α chain and a β-A or a β-B chain; activins are either homodimers of β-A chains or heterodimers of a β-A and a β-B chain. All three chains are related to TGF-β.
• Bone morphogenetic proteins [4] BMP-2, BMP-3 (osteogenin), BMP-3B (GDF-10), BMP-4 (BMP-2B), BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1) and BMP-8 (OP-2) which induce cartilage and bone formation and which are probably involved in the control of the production of skeletal structures during development.
• Embryonic growth factor GDF-1, which may mediate cell differentiation events during embryonic development.
• Growth/development factor GDF-5 [5], a protein whose gene, when mutated in mice, is the cause of brachypodism, a defects which alters the length and numbers of bones in the limbs.
• Growth/development factor GDF-3, GDF-6, GDF-7, GDF-8 (myostatin) and GDF-9.
• Mouse protein nodal, which seems essential for mesoderm formation.
• Chicken dorsalin-1 (dsl-1) which may regulate cell differentiation within the neural tube.
• Xenopus vegetal hemisphere protein Vg1, which seems to induce the overlying animal pole cells to form mesodermal tissue.
• Drosophila decapentaplegic protein (DPP-C), which participates in the establishment of dorsal-ventral specification.
• Drosophila protein screw (scw) which also participates in the establishment of dorsal-ventral specification.
• Drosophila protein 60A.
• Caenorhabditis elegans larval development regulatory growth factor daf-7.
• Mammalian endometrial bleeding-associated factor (EBAF) (Lefty).
• Mammalian glial cell line-derived neurotrophic factor (GDNF), a distantly related member of this family which acts as neurotrophic factor for dopaminergic neurons of the substantia nigra.

Proteins from the TGF-β family are only active as homo- or heterodimer; the two chains being linked by a single disulfide bond. From X-ray studies of TGF-β-2 [6], it is known that all the other cysteines are involved in intrachain disulfide bonds. As shown in the following schematic representation, there are four disulfide bonds in the TGF-βs and in inhibin β chains, while the other members of this family lack the first bond.

                                                     interchain
                                                     |
          +------------------------------------------|+
          |                *******                   ||
 xxxcxxxxxCcxxxxxxxxxxxxxxxxxxCxxCxxxxxxxxxxxxxxxxxxxCCxxxxxxxxxxxxxxxxxxxCxCx
    |      |                  |  |                                        | |
    +------+                  +--|----------------------------------------+ |
                                 +------------------------------------------+

'C': conserved cysteine involved in a disulfide bond.
'*': position of the pattern.

As a pattern to detect these proteins, we use a region which includes two of the conserved cysteines. We also developed a profile that covers all the conserved cysteines.