Structure of plasma and tissue kallikreins

Abstract

The kallikrein kinin system (KKS) consists of serine proteases involved in the production of peptides called kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation. Here we review the protein structural data available for these serine proteases and examine the molecular mechanisms of zymogen activation and substrate recognition focusing on plasma kallikrein (PK) and tissue kallikrein (KLK1) cleavage of kininogens. PK circulates as a zymogen bound to high-molecular-weight kininogen (HK). PK is activated by coagulation factor XIIa and then cleaves HK to generate bradykinin and factor XII to generate further XIIa.A structure has been described for the activated PK protease domain in complex with the inhibitor benzamidine. Kallikrein-related peptidases (KLKs) have a distinct domain structure and exist as a family of 15 genes which are differentially expressed in many tissues and the central nervous system.They cleave a wide variety of substrates including low-molecular-weight kininogen (LK) and matrix proteins. Crystal structures are available for KLK1, 3, 4, 5, 6 and 7 activated protease domains typically in complex with S1 pocket inhibitors. A substrate mimetic complex is described for KLK3 which provides insight into substrate recognition. A zymogen crystal structure determined for KLK6 reveals a closed S1 pocket and a novel mechanism of zymogen activation. Overall these structures have proved highly informative in understanding the molecular mechanisms of the KKS and provide templates to design inhibitors for treatment of a variety of diseases.

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

“…Factor VII-activating protease (FSAP), which is activated upon contact with dead cells, has been demonstrated induce BK generation from HK; however the contribution to BK formation in vivo is not established yet (30,31). Tissue kallikrein 1 (KLK1) has been shown to induce LK cleavage resulting in the liberation of Lys-BK, which may subsequently processed to BK by aminopeptidases (32,33). Pancreas, salivary glands and kidney have been demonstrated to express KLK1 (32,33).…”

“…Tissue kallikrein 1 (KLK1) has been shown to induce LK cleavage resulting in the liberation of Lys-BK, which may subsequently processed to BK by aminopeptidases (32,33). Pancreas, salivary glands and kidney have been demonstrated to express KLK1 (32,33). Similarly to the other members of the tissue kallikrein family, KLK1 is synthesized as zymogen and activated by proteolytic cleavage releasing a hydrophobic residue (33).…”

“…Pancreas, salivary glands and kidney have been demonstrated to express KLK1 (32,33). Similarly to the other members of the tissue kallikrein family, KLK1 is synthesized as zymogen and activated by proteolytic cleavage releasing a hydrophobic residue (33). Despite this unusual activation pattern, it is still not known on whether autoactivation and/or activation by a yet unidentified protease result in KLK1 activation in vivo (33).…”

“…Similarly to the other members of the tissue kallikrein family, KLK1 is synthesized as zymogen and activated by proteolytic cleavage releasing a hydrophobic residue (33). Despite this unusual activation pattern, it is still not known on whether autoactivation and/or activation by a yet unidentified protease result in KLK1 activation in vivo (33). The role of this mainly tissue-restricted kinin generation in the form of Lys-BK in the pathogenesis of C1-inh-mediated angioedema remains to be established.…”

The kallikrein system in retinal damage/protection

“…On the other hand, the tissue kallikrein produces and releases kallidin from low-molecularweight kininogen. Kallidin is converted to bradykinin by aminopeptidase (Pathak et al, 2013). According to a previous study, the tissue kallikrein is expressed in the retina, ciliary muscle, and trabecular meshwork cells (Webb, 2011).…”