cysteïneswitch

Cysteine switch refers to a regulatory mechanism found in certain matrix metalloproteinases (MMPs) and related metalloproteases, whereby a conserved cysteine residue in the pro-domain coordinates with the catalytic zinc ion to keep the enzyme in an inactive, latent state. This “switch” controls when the protease becomes active and capable of substrate processing.

In many MMPs, the pro-domain contains a cysteine that binds to the catalytic zinc, preventing substrate binding and catalytic activity. Activation occurs when the pro-domain is removed or its interaction with zinc is disrupted, allowing the enzyme to adopt an active conformation. This activation can be triggered by proteolytic cleavage or by redox- or environment-dependent changes that break the cysteine–zinc interaction.

A commonly cited motif associated with the cysteine switch is a conserved sequence in the pro-domain, such as PRCGVPD, though variations exist among different MMPs. Activation can occur extracellularly or at other cellular locations, often involving other proteases or cellular processes that process the prodomain.

Biological significance of the cysteine switch lies in its role in controlled extracellular matrix remodeling, angiogenesis, and tissue development. Dysregulation of MMP activation via the cysteine switch has been linked to pathological conditions including cancer invasion and metastasis, fibrosis, and inflammatory diseases.

Related metalloproteases, such as members of the ADAM family, also utilize cysteine-based regulatory mechanisms. In research and engineering contexts, the cysteine switch concept informs strategies to modulate protease activity for therapeutic and biotechnological applications.