KLK14 interactions with HAI‐1 and HAI‐2 serine protease inhibitors: A molecular dynamics and relative free‐energy calculations study

Abstract

Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator-inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA. KLK14 was successfully modeled. Calculated free energies suggested higher binding affinity for the KLK14/HAI-1 interaction than for KLK14/HAI-2. This difference in binding affinity is largely explained by the higher stability of the hydrogen-bond networks in KLK14/HAI-1 along the simulation trajectory. A key arginine residue in both HAI-1 and HAI-2 is responsible for their interaction with the S1 pocket in KLK14. Additionally, MM/GBSA free-energy decomposition postulates that KLK14 Asp174 and Trp196 are hotspots for binding HAI-1 and HAI-2.

Bone Metastasis Phenotype and Growth Undergo Regulation by Micro-Environment Stimuli: Efficacy of Early Therapy with HGF or TGFβ1-Type I Receptor Blockade

“…Under SB431542 plus TGFβ1, the HAI-1 transcript was lower than under the single therapeutic treatment, in agreement with HGF accumulation. HGF is synthesized as a precursor, and Kallikrein 14 at low concentration cleaves pro-HGF into its two-chain active form, but it is also involved in the degradation of HAI-1 [37]. HAI-1 inhibits the pro-HGF activators HGFA (soluble) and the TTSPs Matriptase and hepsin (transmembrane) [19].…”

Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy

“…Identification of loss-of-function SPINT2 mutations in individuals with the syndromic form of CTE suggests that the disease develops in response to an unchecked serine protease activity. In in vitro and in cell culture-based systems, HAI-2 displays potent inhibitory activity towards a large number of membranebound and soluble trypsin-like serine proteases, including hepsin, matriptase, matriptase-2, prostasin, HGFA, coagulation factors IXa, Xa, XIa and XIIa, as well as several members of kallikrein family, presenting a considerable challenge in identification of physiologically relevant inhibitory targets (Beckmann et al, 2016;Delaria et al, 1997;Herter et al, 2005;Kirchhofer et al, 2005;Maurer et al, 2013;Qin et al, 1998;Solis-Calero and Carvalho, 2017;Szabo et al, 2008). However, genetic silencing of HAI-2 in cultured human intestinal epithelial cells was recently shown to increase cleavage of EpCAM by matriptase, causing premature degradation of the tight junction protein claudin 7, thus implicating matriptase hyperactivity in the etiology of the syndromic form of CTE (Wu et al, 2017).…”

Catechol-O-methyl transferase suppresses cell invasion and interplays with MET signaling in estrogen dependent breast cancer

“…Considering the function of SPINT2, its role as tumor suppressor was reported in several malignancies such as breast cancer 38,42 , prostate cancer 43,44 , renal cell carcinoma [45][46][47] , brain cancer [48][49][50][51] and others 52,53 . SPINT2 has been found to be associated with COMT in in silico analysis so far only indirectly through epithelial cell adhesion molecule (EPCAM) and aldehyde dehydrogenase (ALDH) family using STRING database (Fig.…”