355 Chaudhry et al. fill in a key step, showing that a piece of an extracellular matrix (ECM) protein frees inert TGFβ.
TGFβ helps control whether cells move, divide, specialize, and survive. Cells often lock up the potent cytokine by fastening a complex containing its inactive form to fibrillin-1 fibers in the ECM. Discovering how this sequestered TGFβ breaks loose might clarify the mechanism of Marfan's syndrome, in which fibrillin-1 mutations lead to symptoms such as a weakened aorta and leaky heart valves.
Chaudhry et al. demonstrated that fibrillin-1 itself helps release the TGFβ complex. The researchers narrowed this ability to a small fragment of the protein. The segment doesn't bind to TGFβ. Instead, it attaches tightly to the end of fibrillin-1 that carries the cytokine complex. The researchers hypothesize that this interaction alters the shape of full-length fibrillin-1 and dislodges the inert TGFβ. Other enzymes could then activate it.
Fibrillin fragments wouldn't normally be loose in the extracellular matrix, but some fibrillin mutations distort the protein so that it is more likely to be sliced up by ECM enzymes. That might unleash the TGFβ-releasing segment, the researchers speculate.