Protein S Structure and Function. Discovery of Protein S Function. The unraveling of the process of blood coagulation has slowly occurred throughout the 20th century. During the 1970s, the focus slowly began to change to questions dealing with regulatory mechanisms that could be important in thrombotic disease. A search for other inhibitors and/or regulatory factors began concurrent with studies on antithrombin III and its interaction with heparin. With the advent of improved chromatographic tools, it became possible to purify trace proteins and analyze their structures. In the early 1970s, Stenflo purified a new vitamin K-dependent protein that was designated protein C (1). It was observed that proteases like trypsin or thrombin could convert it to a serine protease (2). Kisiel and coworkers (3), closely followed by Walker and co-workers (4), recognized that this protease was unique in that it inhibited blood coagulation and that the mechanism appeared to be through the proteolysis of factor Va. Subsequently, it was observed that factor VIII was also a substrate (5, 6). Interestingly, it was found that the active form of factor Va was a better substrate than the circulating form of factor V (4), and the same was found to be true of factors VIII and Villa (6). Proteolysis of factors Va (4) and Villa (7) was observed to be dependent upon the presence of calcium ions and phospholipid vesicles. In 1980, Walker (8) proposed that activated protein C needed a cofactor protein for the expression of its anticoagulant activity and suggested that this protein was protein S. This discovery evolved from the earlier observations that since proteases derived from vitamin K-dependent proteins, factors Xa, IXa, and Vila, all required cofactor proteins for the maximum expression of their activity, it was possible that activated protein C might also need a cofactor protein.
