The molecular basis for anti-proteolytic and non-proteolytic functions of plasminogen activator inhibitor type-1: roles of the reactive centre loop, the shutter region, the flexible joint region and the small serpin fragment.
The serine proteinase inhibitor plasminogen activator inhibitor type-1 (PAI-1) is the primary physiological inhibitor of the tissue-type and the urokinase-type plasminogen activator (tPA and uPA, respectively) and as such an important regulator of proteolytic events taking place in the circulation and in the extracellular matrix. Moreover, a few non-proteolytic functions have been ascribed to PAI-1, mediated by its interaction with vitronectin or the interaction between the uPA-PAI-1 complex bound to the uPA receptor and members of the low density lipoprotein receptor family. PAI-1 belongs to the serpin family, characterised by an unusual conformational flexibility, which governs its molecular interactions. In this review we describe the anti-proteolytic and non-proteolytic functions of PAI-1 from both a biological and a biochemical point of view. We will relate the various biological roles of PAI-1 to its biochemistry in general and to the different conformations of PAI-1 in particular. We put emphasis on the intramolecular rearrangements of PAI-1 that are required for its antiproteolytic as well as its non-proteolytic functions.
Wind
Troels
T
Department of Molecular and Structural Biology, Aarhus University, Denmark.
Hansen
Martin
M
Jensen
Jan K
JK
Andreasen
Peter A
PA
D000818:Animals; D002448:Cell Adhesion; D004705:Endocytosis; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism; D013329:Structure-Activity Relationship
D017395:Plasminogen Activator Inhibitor 1; D011973:Receptors, LDL