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Computational characterization and integrative analysis of proteins involved in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Pranitha Jenardhanan, Manivel Panneerselvam, Premendu P. Mathur
In addition to the studies aimed at improving efficacy of adjudin, other studies were also conducted to identify new promising leads that can be used as male contraceptives. In a study conducted by Jenardhanan et al., the authors analyzed the structure of MARK4,114 which is shown to be important in conferring polarity to maturing spermatids that are attached with apical ES and targeted inhibition of MARK4 is shown to impair spermatogenesis, resulting in premature release of immature spermatid into the lumen. In this study, the authors predicted the three-dimensional conformation for the kinase-UBA construct of MARK4 and identified MARK4-specific inhibitors.114 MARK4 belongs to the serine/threonine kinases and is the mammalian homolog of partition-defective 1 protein. MARK4 has four important regions: N-terminal kinase domain, autoregulatory UBA domain, disordered spacer region, and a terminal kinase-associated domain. As a means of identifying novel inhibitors for MARK4, the authors have predicted the structure for the kinase–UBA construct in an inactive catalytic conformation and revealed that MARK4 has unique structural features such as DFG-in-αC-helix-out inactive conformation that differentiates it from other ser/thr kinases. The presence of a unique DFG-in-αC-helix-out mode necessitates the design of MARK-specific inhibitors. In doing this, the authors utilized the pharmocophoric feature of 9-oxo derivatives that are shown to be MARK-specific and used them to screen a library of kinase inhibitors. The results identified 10 potent leads that on molecular dynamics simulation study maintained their binding association and showed steady pulling of N- and C-terminal lobes of kinase domain, thereby arresting the catalytic conformation from phosphorylating its substrates. The identified leads function as potent ATP competitors such that with unique DFG-in conformation they can be used to inhibit both active and inactive states of MARK4, thus favoring their selection for the design of next generation nonhormonal contraceptives. There are few studies that illustrate how structural bioinformatics can be used to understand the underlying structural mechanism behind the biological function of selected biomarkers.
Microtubule affinity regulating kinase 4 promoted activation of the NLRP3 inflammasome-mediated pyroptosis in periodontitis
Published in Journal of Oral Microbiology, 2022
Lulu Wang, Wenchen Pu, Chun Wang, Lang Lei, Houxuan Li
MARK4 regulates the NLRP3 positioning and inflammasome activation mainly in a microtubule-dependent manner in macrophages [16]. MARK4 mainly regulates the microtubule dynamic by phosphorylating the microtubule-associated proteins (MAPs) and causes the detachment of MAPs from microtubules [15]. MARK4 participates in the high glucose-induced NLRP3 inflammasome activation, thus mediating IL-1β and IL-18 expression in vascular endothelial cells [23]; in addition, MARK4 deficiency inhibited hypoxia/reoxygenation (H/R)-induced NLRP3 inflammasome activation [39]; moreover, positive MARK4 expression has been observed in human atherosclerotic lesions, and MARK4 deficiency in BMDMs reduced cholesterol crystal-induced NLRP3 inflammasome activation [16]. Our present study further demonstrated that MARK4 has been implicated in bacteria-induced inflammasome activation in periodontitis. Upon inhibition of MARK4, improper positioning of NLRP3 will destroy the assembly of NLRP3 inflammasome along microtubules in the centrosome, eventually attenuating inflammasome activation [21].
The role of microtubules in the regulation of epithelial junctions
Published in Tissue Barriers, 2018
Ekaterina Vasileva, Sandra Citi
Microtubule affinity-regulating kinases (MARKs) are an evolutionarily conserved family of kinases that comprise MARK1(PAR-1c), MARK2 (PAR-1b/EMK), MARK3 (PAR-1a/C-TAK1) and MARK4 (PAR-1d/MARKL1).152 Mammalian MARKs are homologous to the invertebrate partitioning gene product Par-1, which regulates development of cell polarity,153 and belong to the same family of energy sensing kinases as AMPK.154 MARKs are indirectly associated with MTs, since they were identified as kinases that phosphorylate the MT-regulating proteins tau and MAPs, to regulate MT dynamics and MT-dependent transport.155 There is evidence that MARK proteins are involved in different aspects of epithelial differentiation. For example, MARK4 localizes to the basal body and promotes ciliogenesis in ciliated cells,156 and MARK2 functions downstream of aPKC in the establishment and maintenance of epithelial cell polarity in mammalian cells157 (Figure 3). Importantly, MARK2 (PAR1b) has been localized both at apical and lateral epithelial junctions,157 and is required for the formation of apical lumens in epithelial cells grown in 3D, by promoting the apicobasal alignment of MTs, and by modulating myosin-II and E-cadherin dependent signaling158,159 (Figure 3). MARKs are involved in regulation of different signaling pathways, for example through the phosphorylation of proteins involved in membrane recycling,160 RhoA/Rac1 signaling,115,161,162 inflammation,163 and the Hippo pathway.164 However, although MARK2 has been localized at junctions,157,158 little is known about the junctional localization of other MARKs (MARK1, MARK3 and MARK4), the mechanisms that regulate the subcellular localizations of MARKs, and the effect of junctional localization on the enzymatic activity and signaling functions of MARK proteins.