What is Serpin Family?

Serpin, a class of protease inhibitors with a molecular weight of 40-50 kDa, widely exists in various organisms, is considered to be an important factor involved in immune regulation and other biological pathways. The irreversibility of inhibition achieved by the serpins has made them the principal inhibitors controlling both intra- and extracellular proteolytic pathways. In mammals, serpins are expressed in many tissues and they regulate the activities of a diverse array of serine and cysteine proteases, controlling complement activation, blood coagulation, fibrinolysis, inflammation, tumor cell metastasis, apoptosis, neurite extension, and many other physiological processes.

Fig 1 Model demonstrating possible molecular basis of SerpinE2 induced collagen deposition in myocardial fibrosis

Serine proteinase inhibitors (serpins), typically fold to a metastable native state and undergo a major conformational change in order to inhibit target proteases. However, conformational lability of the native serpin fold renders them susceptible to misfolding and aggregation, and underlies misfolding diseases such as α1-antitrypsin deficiency. Serpin specificity towards its protease target is dictated by its fexible and solvent exposed reactive centre loop (RCL), which forms the initial interaction with the target protease during inhibition.

The SCC Ag-1, a member of the human serpin family and a tumour-associated protein, is functionally linked to the apoptotic pathway(s) in squamous cell carcinoma and other tumour cells. The expression level of the SCC Ag-1 in cancer cells appears to be, in part, responsible for resistance of these cells to apoptosis in vitro and to tumour progression and growth in vivo.

PEDF is a member of the serpin superfamily that has many functions that often act in opposition to mechanisms that drive cancer progression. Tumour progression is associated with reduced levels of PEDF in tumours. Exogenous administration of PEDF to bolster the declining intratumoural levels of PEDF during tumour progression results in the inhibition of tumour growth and prolonged organismal survival in various animal models.

Fig 2 PEDF in tumour cells

The understanding of the structure and mechanism of serpin action will help us to find effective drug therapeutic targets against some diseases, such as cancer.