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Genetics of heart failure
Published in ILEANA PIÑA, SIDNEY GOLDSTEIN, MARK E DUNLAP, The Year in Heart Failure, 2005
RAY HERSHBERGER, EMILY BURKETT
This work suggests that disruption of the Cypher/ZASP gene is responsible for approximately 6o/o of cases of left ventricular dysfunction (DCM or INLVM). This gene encodes a specific Z-line PDZ-domain protein that plays a potentially important role in bridging the sarcomere to the cytoskeletal network. This supports the concept that disruption of the cytoarchitecture, comprising the cytoskeleton, sarcolemma and interacting components, is pivotal to the development of LV dysfunction.
Rabies and other lyssaviruses
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Thiravat Hemachudha, Jiraporn Laothamatas, Henry Wilde
Neuronal integrity needs to be preserved for efficient viral propagation. Apoptosis is not present in the case of street rabies virus infection. This is dependent on restricted expression of the G protein and G gene sequence including four amino acids at carboxyl-terminal PDZ domain-binding motif (PDM) that can bind cellular PDZ proteins, which control cell polarity and apoptosis [47,77,80]. Delayed apoptosis and higher pathogenicity of street strain may be correlated with the matrix protein gene residues R77 and E81 [79]. Thus, during the asymptomatic period, neurons do not exhibit cytopathic changes and remain metabolically viable in vivo. They express their neurotransmitters and transport other markers [40–42,46,81,82]. However, during the severe symptomatic phase, wild-type viral infection in mice results in alteration of host proteins expression, especially those involved in ion homeostasis and docking and fusion of synaptic vesicles to presynaptic membranes [83]. This may lead to defective neurotransmission recognized in rabies [70]. Oxidative damage may also cause neuronal dysfunction [84,85]. In moribund mice, mild structural damage involving neuronal processes, such as beading and fragmentation of axons and dendrites, with vacuoles that correspond to swollen mitochondria, was identified [86]. This was demonstrated, in vitro, to be the result of oxidative stress through virus-induced inhibition of NF-κB signaling, which plays a critical role in axonal growth, neuronal survival, and antiviral responses [84,85]. Nevertheless, the most plausible mechanism in explaining coma is impaired mitochondrial function and consequently bioenergetics failure.
Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
There is an event taking place in the cytoplasm, which bridges the activation of FZD/LRP receptors and the inhibition of β-catenin destruction complex. A key protein involved in this process is Dishevelled (DVL1–3 in human, Dsh in Drosophila), which is a cytosolic phosphoprotein working upstream of Axin-APC-CSK1α-GSK-3 inhibition in both fly and mammalian cells (23). It is 700 amino acids in size and consists of three main domains, each composed of about 80–90 amino acids: DIX (Dishevelled, Axin), PDZ (Postsynaptic density 95, disc large, zona occudens-1) and DEP (Dishevelled, Egl-10, Pleckstrin) (28). The PDZ domain is the key domain for signal transduction as it interacts directly with the intracellular domain of Frizzled (20). After the successful binding of Wnt to FZD, the first intracellular step is the activation of DVL proteins, which phosphorylate the intracellular domain of LRP5/6. While the requirement of Dishevelled in Wnt signaling has long been known, the molecular events involved in the activation of Dsh by Frizzled and the manner in which it transduces the Wnt signal to the inhibitory complex need to be explored. There are several reports on the physical association between FZD and Dsh and the Wnt-dependent phosphorylation of Dsh (29). Another protein that plays a key role in linking receptor activation to inhibition of the β-catenin destruction complex is Axin, which is a member of the destruction complex itself. It was shown that Axin binds directly to the intracellular domain of LRP in response to Wnt reception (30). The phosphorylation of LRP on key residues by the kinases CK1 and GSK-3 leads to the recruitment of Axin to LRP (31). Overexpression of the membrane-bound form of the LRP intracellular domain can lead to β-catenin accumulation, even in the absence of FZD and DVL, indicating that the recruitment of Axin to the intracellular domain of LRP is sufficient to activate Wnt signaling (32).
Tight junctions: from molecules to gastrointestinal diseases
Published in Tissue Barriers, 2023
Aekkacha Moonwiriyakit, Nutthapoom Pathomthongtaweechai, Peter R. Steinhagen, Papasara Chantawichitwong, Wilasinee Satianrapapong, Pawin Pongkorpsakol
Zonula occludens (ZO), including ZO-1 and its homologs ZO-2 and ZO-3, is a group of PDZ-related scaffolding proteins that belong to the superfamily of membrane-associated guanylate kinase-like proteins, possessing sites of three tandem PDZ domains at the N-terminus38,39 (Figure 1). The first PDZ domain interacts with claudins, the binding affinity of which is regulated by phosphorylation at the PDZ-binding motifs of claudins.40 The second PDZ domain establishes dimerization with another PDZ2, while PDZ3 is bound by JAM-A. In addition to PDZ regions, ZO-1 engages with other scaffolding proteins and cytoskeletal components, such as afadin, occludin, and α-catenin, through Src homology 3 (SH3), U5, guanylate kinase-like (GUK) regions, and actin-binding region (ABR).41,42 Moreover, the interactive zone of PDZ3 together with SH3-GUK-U6 facilitates the phase separation of ZO-1 and polymerization of ZO proteins during ZO assembly.43,44
Functional analysis and cryo-electron microscopy of Campylobacter jejuni serine protease HtrA
Published in Gut Microbes, 2020
Urszula Zarzecka, Alessandro Grinzato, Eaazhisai Kandiah, Dominik Cysewski, Paola Berto, Joanna Skorko-Glonek, Giuseppe Zanotti, Steffen Backert
All bacteria have effective stress responses to limit protein damage under harsh environmental conditions. In addition to the common cytoplasmic stress response proteins (DnaK, GroES/EL, GrpE, DnaJ, ClpB, etc.),19,20 the HtrA (high-temperature requirement A) protein plays an important protective function in the cellular envelope. This protein exhibits both protease and chaperone activities and is found in almost all bacteria.21 The best-characterized member of this protein family is HtrA from Escherichia coli (HtrAEc, also known as DegP).22,23 As a protein quality control factor, DegP recognizes and degrades proteins that are not properly folded. In particular, DegP preferentially digests unfolded polypeptides with exposed hydrophobic residues and it mainly hydrolyzes peptide bonds after hydrophobic amino acid residues.24 A characteristic feature of the HtrA family of proteins is the presence of a chymotrypsin-type protease domain as well as one or two C-terminal PDZ domains (Postsynaptic density protein 95, Drosophila disc large tumor suppressor and Zonula occludens-1 protein domain).25 PDZ domains are typically involved in substrate binding, regulation of the proteolytic activity and inter-subunitinteractions.26
Phosphorylation of tight junction transmembrane proteins: Many sites, much to do
Published in Tissue Barriers, 2018
Christina M. Van Itallie, James M. Anderson
PDZ-dependent interactions are a central feature of tight junction organization. Many tight junction scaffolding proteins, including ZO proteins,15-17 MUPP1,18 afadin/AF6,19 MAGI-1, 2, 3,20–22 PARD3,23 PALS124 and PATJ25 among others, contain multiple PDZ domains. PDZ domains form small globular structures of 80–90 residues;26 which typically bind the 4–10 carboxy-terminal residues (PDZ binding motifs)27,28 of transmembrane proteins and anchor them to the junction. The basic model for interaction is that the terminal hydrophobic residue of the PDZ binding motif-containing protein (numbered amino acid 0) inserts into a hydrophobic pocket in the PDZ domain, and then the upstream amino acids of the binding motif (-1 to -5) form an antiparallel beta strand to a beta strand in the PDZ domain.29 Both the tight junction strand forming cldns6 and the adhesion proteins, the JAMs8,9 end in PDZ binding motifs and have been shown to interact with the PDZ domain-containing scaffolding proteins.