Structural basis of profactor D activation: From a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D

Academic Article

Abstract

  • The crystal structure of profactor D, determined at 2.1 Å resolution with an R(free) and an R-factor of 25.1 and 20.4%, respectively, displays highly flexible or disordered conformation for five regions: N-22, 71-76, 143-152, 187-193 and 215-223. A comparison with the structure of its mature serine protease, complement factor D, revealed major conformational changes in the similar regions. Comparisons with the zymogen-active enzyme pairs of chymotrypsinogen, trypsinogen and prethrombin-2 showed a similar distribution of the flexible regions. However, profactor D is the most flexible of the four, and its mature enzyme displays inactive, self-inhibited active site conformation. Examination of the surface properties of the N-terminus-binding pocket indicates that Ile16 may play the initial positioning role for the N-terminus, and Leu17 probably also helps in inducing the required conformational changes. This process, perhaps shared by most chymotrypsinogen-like zymogens, is followed by a factor D-unique step, the re-orientation of an external Arg218 to an internal position for salt-bridging with Asp189, leading to the generation of the self-inhibited factor D.
  • Published In

  • EMBO Journal  Journal
  • Digital Object Identifier (doi)

    Author List

  • Jing H; Macon KJ; Moore D; DeLucas LJ; Volanakis JE; Narayana SVL
  • Start Page

  • 804
  • End Page

  • 814
  • Volume

  • 18
  • Issue

  • 4