A Structural Network Associated with the Kallikrein-kinin and Renin-angiotensin Systems

The kallikrein-kinin and renin-angiotensin (KKS-RAS) systems represent two highly regulated proteolytic systems that are involved in several physiological and pathological processes. Although their protein-protein interactions can be studied using experimental approaches, it is difficult to differentiate between direct physical interactions and functional associations, which do not involve direct atomic contacts between macromolecules. This information can be obtained from an atomic-resolution characterization of the protein interfaces. As a result of this, various three-dimensional-based protein-protein interaction databases have become available. To gain insight into the multilayered interaction of the KKS-RAS systems, we present a protein network that is built up on three-dimensional domain-domain interactions. The essential domains that link these systems are as follows: Cystatin, Peptidase_C1, Thyroglobulin_1, Insulin, CIMR (Cation-independent mannose-6-phosphate receptor repeat), fn2 (Fibronectin type II domain), fn1 (Fibronectin type I domain), EGF, Trypsin, and Serpin. We found that the CIMR domain is located at the core of the network, thus connecting both systems. From the latter, all domain interactors up to level 4 were retrieved, thus displaying a more comprehensive representation of the KKS-RAS structural network.