State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yang Qiao West Road, Fuzhou, Fujian, 350002, China.
Biochem J. 2013 Jan 1;449(1):161-6. doi: 10.1042/BJ20121132.
An important regulatory mechanism of serine proteases is the proteolytic conversion of the inactive pro-enzyme, or zymogen, into the active enzyme. This activation process is generally considered an irreversible process. In the present study, we demonstrate that an active enzyme can be converted back into its zymogen form. We determined the crystal structure of uPA (urokinase-type plasminogen activator) in complex with an inhibitory antibody, revealing that the antibody 'rezymogenizes' already activated uPA. The present study demonstrates a new regulatory mechanism of protease activity, which is also an extreme case of protein allostery. Mechanistically, the antibody binds a single surface-exposed loop, named the autolysis loop, thereby preventing the stabilization of uPA in its active conformation. We argue that this autolysis loop is a key structural element for rezymogenation of other proteases, and will be a new target site for pharmacological intervention with serine protease activity.
丝氨酸蛋白酶的一个重要调控机制是将无活性的原酶（酶原）切割转化为有活性的酶。这一激活过程通常被认为是一个不可逆的过程。在本研究中，我们证明了一种活性酶可以被重新转化为其酶原形式。我们确定了与抑制性抗体结合的 uPA（尿激酶型纤溶酶原激活物）的晶体结构，揭示了抗体“再酶原化”已经激活的 uPA。本研究证明了蛋白酶活性的一种新调控机制，这也是蛋白质变构作用的一个极端案例。从机制上讲，抗体结合到一个单一的暴露于表面的环，即自溶环，从而阻止 uPA 稳定在其活性构象中。我们认为这个自溶环是其他蛋白酶再酶原化的关键结构元件，也将成为丝氨酸蛋白酶活性的药理学干预的新靶点。
