Molecular structure

The TGF|3 superfamily consists of a number of structurally related regulatory proteins which, besides TGFp, to TGF(3S, include the inhibins, activins, bone inorphogenic proteins and related morphogenic proteins, which are all of importance in many areas of cell biology. The five isoforms of TGFp share biological activities. The prototype of this family is TGFPi, originally purified from human platelets. These represent the most concentrated natural source of TGFp. Only TGFp,, TGFp2 and TGFp, have been identified and cloned in mammalian species, whereas TGFp4 and TGFp5 have been found only in chick and Xenopus, respectively. The genes for each of the mammalian isoforms are located on different chromosomes: TGFp | on chromosome 19, TGFp2 on chromosome 1, and TGFp, on chromosome 14.

TGFp | is a disulfide-linked homodimer of the C-terminal 112 amino acids (12.5 kDa) derived from a 390 amino acid precursor peptide (Table 1). The processed mature TGFp homodimer (25 kDa) is biologically inactive or latent when noncovalently associated with the N-terminal part of the dimeric precursor, the latency-associated peptide (P-LAP), which is linked by disulfide bond(s) to a third molecule termed the latent TGFp-binding protein (LTBP). LTBP is a 125-160 kDa protein containing epidermal growth factor (EGF)-like repeats.

Activation of TGFp occurs by dissociation of the mature dimer from the P-LAP by exposure in vitro to pH changes, heat, urea or SDS. The mechanisms for activation in vivo, e.g. in the context of inflammation, are incompletely understood. There is evi-

Table 1 Physicochemical properties of human TGFß,, TGFß., and TGFßa
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