Integrin Expression in Tumor Progression — Role of Signaling Mechanisms
Róza Ádány in Tumor Matrix Biology, 2017
The cytoplasmic domains of the integrins are short (50 amino acids), except β4, which is characterized by a 1000-amino acid long sequence containing a tyrosine phosphorylation sequence.2,13 The cytoplasmic domain of the integrins interacts with several linker proteins to form connections with the actin cytoskeleton. These linker molecules include α-actinin,17 talin,18 vinculin,19 and fibulin,20 as well as kinases such as protein kinase C (PKC), protein tyrosine kinase (PTK), and focal adhesion kinase (FAK).21 It is important to underline that the cytoplasmic interactions seem to be dependent on the cytoplasmic domain of the α chain, resulting in similar ligands recognizing heterodimers with altered cytoskeletal connections (α5β1/α3/β1 and αvβ3/αvβ5). Unlike most of the integrins interacting with actincytoskeleton, α6β4 exhibits specific interactions with intermediate filaments in hemidesmosomes, determined by its unique cytoplasmic domains.12 These cytoplasmic interactions are likely to mediate signal transduction from the exterior to the interior of the cell as well as from the interior to the exterior of the cell (i.e., outside-in and inside-out signalings).12,22 At present the function of the transmembrane domain is unknown besides its role as a linker between the extracellular and cytoplasmic domains.
Molecular Biology of Calcium Pumps in Myometrium
Robert E. Garfield, Thomas N. Tabb in Control of Uterine Contractility, 2019
Conclusive statements on the topological arrangement of the transmembrane domains require more information, and advances in this area are now being made by using antibodies raised against peptides corresponding to selected domains of the pump.18 Feschenko et al. have recently described a monoclonal antibody against human erythrocyte Ca2+ pump that has reacted with the enzyme in intact erythrocytes.18 Based on proteolysis of the pump protein and sequencing of amino acids, the location of this epitope has been mapped to a 13 residue sequence starting at Glul30 and ending at Glul42. In Figure 2 this domain is located between transmembrane domains 1 and 2 on the extracellular surface.
Cyclic Nucleotides
Enrique Pimentel in Handbook of Growth Factors, 2017
The amino acid sequence of guanylyl cyclase, as deduced from a cDNA cloned from sea urchin spermatozoa, predicts an intrinsic membrane protein of 986 amino acids, including an amino-terminal signal sequence.159 A single transmembrane domain separates the protein into putative extracellular and cytoplasmic-catalytic domains. The cytoplasmic carboxyl terminal of 95 amino acids contains 20% serine, which represents regulatory sites for phosphorylation. The guanylyl cyclase protein exhibits structural homology to some members of the protein kinase family, including the PDGF receptor, the Fes tyrosine kinase, and the Mos serine/threonine kinase.
Targeting FGFR in intrahepatic cholangiocarcinoma [iCCA]: leading the way for precision medicine in biliary tract cancer [BTC]?
Published in Expert Opinion on Investigational Drugs, 2021
Gabriella Aitcheson, Amit Mahipal, Binu V John
All four FGFRs – FGFR1, FGFR2, FGFR3, and FGFR4 – are homologous single-pass membrane proteins comprised of an intracellular tyrosine-kinase domain, a transmembrane domain, and an extracellular ligand-binding domain (Figure 3). The extracellular domain is comprised of three immunoglobulin (Ig)-like subunits D1, D2 and D3 with D2 and D3 forming the FGF binding pocket [34,35]. The linker region between D1 and D2 is called the acid box and plays a role in autoinhibition via conformational changes in the receptor though the mechanism remains to be fully understood [36,37]. The transmembrane domain contains a single helix that traverses the cell membrane. The intracellular tyrosine-kinase domain consists of a small N-terminal lobe and a larger C-terminal lobe that are linked together by a hinge. The area between these two lobes contains the active site where ATP and the substrate protein bind[38]. The N-terminal lobe includes the nucleotide binding loop (P-loop) which encloses ATP to glean its phosphate and the αC-helix which plays a role in regulation [38,39]. The C-terminal lobe is made up of mainly seven alpha helices, but most importantly contains the catalytic loop and activation loop (A-loop) which regulate FGFR activation[38]. The A-loop harbors the DFG-motif conformation made of aspartate, phenylalanine, and glycine (Asp-Phe-Gly) which takes on the active DFG-in state or inactive DFG-out state. In the active DFG-in form, the aspartate residue participates in ATP binding. The subsequent phosphorylation is catalyzed by the aspartate residue in the HRD-motif (His-Arg-Asp) of the catalytic loop.
Computational modeling – an approach to the development of blood grouping reagents
Published in Expert Review of Hematology, 2021
Serena Ekman, Robert Flower, Ross T Barnard, Alison Gould, Xuan T Bui
X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy have been used previously to identify blood group protein structures [8–11]. However, these techniques have proven to be difficult to apply to blood group proteins due to the need for crystallized or highly homogeneous samples. Additionally, membrane-bound proteins are difficult to isolate for crystallography [12] and for multi-pass transmembrane proteins the expression of the extracellular domain alone is unsuitable, similarly for proteins that require the transmembrane domain for stabilization. The emerging field of cryo-electron microscopy (cryoEM) shows much promise for blood group proteins as it allows for both membrane-bound structures and higher levels of heterogeneity [13–15]. The presence (or absence) of glycosylation can play a crucial factor in stabilizing the epitopes of blood group proteins [16]; however, heavy glycosylation hinders the formation of crystals and increases the difficulty in obtaining models for both physical techniques such as NMR or cryoEM, and in some instances proteins need to be deglycosylated before a structure can be obtained [17].
CAR-NK cells: a promising cellular immunotherapy in lymphoma
Published in Expert Opinion on Biological Therapy, 2023
Shaghayegh Khanmohammadi, Nima Rezaei
As mentioned before, CAR is a genetically engineered transmembrane receptor. A CAR has four main components [6]: (1) extracellular binding domain, (2) hinge region, (3) transmembrane domain, and (4) intracellular signaling domain(s). The extracellular binding domain contains a single-chain variable fragment (scFv) derived from tumor-specific antibodies. The transmembrane domain anchors the receptor on the cell membrane of the effector cell. After the recognition of tumor antigen by CAR, the intracellular activation domain(s) leads to the activation of downstream pathways (Figure 1) [6]. The first generation of CAR-NK cells only contains CD3ζ in the intracellular activation domain. In the second and third generation of CAR NK cells, one (second) or two (second) additional co-stimulatory molecules (e.g. CD28, ICOS, 4–1BB, CD27, OX40, and CD40) are present in the activation signaling domain. The presence of co-stimulatory molecules enhanced the activation, expansion, and survival of the cells. The fourth generation of CAR-NK cells can secrete cytokines that increase their persistence and anti-tumor activity. More than one co-stimulatory molecule, such as CD134, CD28, or CD137, is present in the fourth-generation CAR-NK cells, which enhances the anti-tumor activity of CAR-NK cells via the stimulation of the innate immune system [7,35,36].
Related Knowledge Centers
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- Transmembrane Protein
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- Hydrophobicity Scales
- Ion
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