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Chen Liang - One of the best experts on this subject based on the ideXlab platform.
the Transmembrane Domain of bst 2 determines its sensitivity to down modulation by human immunodeficiency virus type 1 vpuJournal of Virology, 2009Co-Authors: Liwei Rong, Jianyong Zhang, Jennifer Lu, Renepierre Lorgeoux, Claudette Aloysius, Mark A Wainberg, Chen LiangAbstract:
Bone marrow stromal cell antigen 2 (BST-2, also known as tetherin) restricts the production of a number of enveloped viruses by blocking virus release from the cell surface. This antiviral activity is counteracted by such viral factors as Vpu of human immunodeficiency virus type 1 (HIV-1). Here, we report that Vpu antagonizes human BST-2 but not BST-2 derived from African green monkeys. The determinants of susceptibility to Vpu map to the Transmembrane Domain of BST-2. In accordance with this, expression of human BST-2 containing a modified Transmembrane Domain effectively blocks the replication of wild-type Vpu-expressing HIV-1 in CD4+ T cells. Furthermore, these BST-2 variants, as opposed to wild-type human BST-2, are refractory to Vpu-mediated down-regulation as a result of an attenuated interaction with Vpu. In view of the work by others pointing to a key role of the Transmembrane Domain of Vpu in promoting virus release, our data suggest that a direct interaction through the Transmembrane Domain of each of these two proteins is a prerequisite for Vpu to down-modulate BST-2.
Eok-soo Oh - One of the best experts on this subject based on the ideXlab platform.
Syndecan Transmembrane Domain modulates intracellular signaling by regulating the oligomeric status of the cytoplasmic Domain.Cellular Signalling, 2018Co-Authors: Bohee Jang, Hyejung Jung, Heejeong Hong, Eok-soo OhAbstract:
Abstract Cell surface receptors must specifically recognize an extracellular ligand and then trigger an appropriate response within the cell. Their general structure enables this, as it comprises an extracellular Domain that can bind an extracellular ligand, a cytoplasmic Domain that can transduce a signal inside the cell to produce an appropriate response, and a Transmembrane Domain that links the two and is responsible for accurately delivering specific information on a binding event from the extracellular Domain to the cytoplasmic Domain, to trigger the proper response. A vast body of research has focused on elucidating the specific mechanisms responsible for regulating extracellular binding events and the subsequent interactions of the cytoplasmic Domain with intracellular signaling. In contrast, far less work has focused on examining how the Transmembrane Domain links these Domains and delivers the necessary information. In this review, we propose the importance of the Transmembrane Domain as a signal regulator. We highlight the cell adhesion receptor, syndecan, as a special case, and propose that the Transmembrane Domain-mediated oligomerization of the syndecan cytoplasmic Domain is a unique regulatory mechanism in syndecan signaling.
The Scientific World Journal, 2006Co-Authors: Jae Youn Yi, Eok-soo OhAbstract:
Cell surface adhesion receptors of the syndecan family initiate intracellular events through clustering of receptors. This crucial clustering occurs through receptor dimerization or oligomerization, which is mediated by receptor Transmembrane Domains. However, the exact role of the Transmembrane Domain during receptor activation is not fully understood. Researchers have not yet determined whether the Transmembrane Domain functions solely in the physical aspects of receptor clustering, or whether the Domain has additional functional roles. Here we review recent advances in understanding the functionality of Transmembrane Domain–dependent oligomerization of syndecan cell adhesion receptor.
Transmembrane Domain induced oligomerization is crucial for the functions of syndecan 2 and syndecan 4Journal of Biological Chemistry, 2005Co-Authors: Sungmun Choi, Jae Youn Yi, Soojin Kwon, Haein Park, Eok-soo OhAbstract:
Abstract The syndecans are known to form homologous oligomers that may be important for their functions. We have therefore determined the role of oligomerization of syndecan-2 and syndecan-4. A series of glutathione S-transferase-syndecan-2 and syndecan-4 chimeric proteins showed that all syndecan constructs containing the Transmembrane Domain formed SDS-resistant dimers, but not those lacking it. SDS-resistant dimer formation was hardly seen in the syndecan chimeras where each Transmembrane Domain was substituted with that of platelet-derived growth factor receptor (PDGFR). Increased MAPK activity was detected in HEK293T cells transfected with syndecan/PDGFR chimeras in a syndecan Transmembrane Domain-dependent fashion. The chimera-induced MAPK activation was independent of both ligand and extracellular Domain, implying that the Transmembrane Domain is sufficient to induce dimerization/oligomerization in vivo. Furthermore, the syndecan chimeras were defective in syndecan-4-mediated focal adhesion formation and protein kinase Cα activation or in syndecan-2mediated cell migration. Taken together, these data suggest that the Transmembrane Domains are sufficient for inducing dimerization and that Transmembrane Domain-induced oligomerization is crucial for syndecan-2 and syndecan-4 functions.
Benjamin F. Cravatt - One of the best experts on this subject based on the ideXlab platform.
Comparative characterization of a wild type and Transmembrane Domain-deleted fatty acid amide hydrolase: identification of the Transmembrane Domain as a site for oligomerizationBiochemistry, 1998Co-Authors: Matthew P. Patricelli, Hilal A. Lashuel, Dan K. Giang, Jeffery W. Kelly, Benjamin F. CravattAbstract:
Fatty acid amide hydrolase (FAAH) is an integral membrane protein responsible for the hydrolysis of a number of primary and secondary fatty acid amides, including the neuromodulatory compounds anandamide and oleamide. Analysis of FAAH's primary sequence reveals the presence of a single predicted Transmembrane Domain at the extreme N-terminus of the enzyme. A mutant form of the rat FAAH protein lacking this N-terminal Transmembrane Domain (¢TM-FAAH) was generated and, like wild type FAAH (WT-FAAH), was found to be tightly associated with membranes when expressed in COS-7 cells. Recombinant forms of WT- and ¢TM-FAAH expressed and purified from Escherichia coli exhibited essentially identical enzymatic properties which were also similar to those of the native enzyme from rat liver. Analysis of the oligomerization states of WT- and ¢TM-FAAH by chemical cross-linking, sedimentation velocity analytical ultracentrifugation, and size exclusion chromatography indicated that both enzymes were oligomeric when membrane-bound and after solubilization. However, WT-FAAH consistently behaved as a larger oligomer than ¢TM-FAAH. Additionally, SDS-PAGE analysis of the recombinant proteins identified the presence of SDS-resistant oligomers for WT-FAAH, but not for ¢TM-FAAH. Self-association through FAAH's Transmembrane Domain was further demonstrated by a FAAH Transmembrane Domain-GST fusion protein which formed SDS-resistant dimers and large oligomeric assemblies in solution.
comparative characterization of a wild type and Transmembrane Domain deleted fatty acid amide hydrolase identification of the Transmembrane Domain as a site for oligomerizationBiochemistry, 1998Co-Authors: Matthew P. Patricelli, Hilal A. Lashuel, Dan K. Giang, Jeffery W. Kelly, Benjamin F. CravattAbstract:
Fatty acid amide hydrolase (FAAH) is an integral membrane protein responsible for the hydrolysis of a number of primary and secondary fatty acid amides, including the neuromodulatory compounds anandamide and oleamide. Analysis of FAAH's primary sequence reveals the presence of a single predicted Transmembrane Domain at the extreme N-terminus of the enzyme. A mutant form of the rat FAAH protein lacking this N-terminal Transmembrane Domain (ΔTM-FAAH) was generated and, like wild type FAAH (WT-FAAH), was found to be tightly associated with membranes when expressed in COS-7 cells. Recombinant forms of WT- and ΔTM-FAAH expressed and purified from Escherichia coli exhibited essentially identical enzymatic properties which were also similar to those of the native enzyme from rat liver. Analysis of the oligomerization states of WT- and ΔTM-FAAH by chemical cross-linking, sedimentation velocity analytical ultracentrifugation, and size exclusion chromatography indicated that both enzymes were oligomeric when membra...
Paul D Bieniasz - One of the best experts on this subject based on the ideXlab platform.
species specific activity of hiv 1 vpu and positive selection of tetherin Transmembrane Domain variantsPLOS Pathogens, 2009Co-Authors: Matthew W Mcnatt, Trinity M Zang, Theodora Hatziioannou, Mackenzie Bartlett, Ismael Farouck Fofana, Welkin E Johnson, Stuart J D Neil, Paul D BieniaszAbstract:
Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of Transmembrane Domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein Domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the Transmembrane Domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin Transmembrane Domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, Transmembrane and cytoplasmic Domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the Transmembrane Domains found in human/chimpanzee tetherin proteins.
Huilin Li - One of the best experts on this subject based on the ideXlab platform.
Nature, 2020Co-Authors: Xiang Feng, Amanda Kovach, Huilin LiAbstract:
The endoplasmic reticulum (ER) membrane complex (EMC) cooperates with the Sec61 translocon to co-translationally insert a Transmembrane helix (TMH) of many multi-pass integral membrane proteins into the ER membrane, and it is also responsible for inserting the TMH of some tail-anchored proteins1-3. How EMC accomplishes this feat has been unclear. Here we report the first, to our knowledge, cryo-electron microscopy structure of the eukaryotic EMC. We found that the Saccharomyces cerevisiae EMC contains eight subunits (Emc1-6, Emc7 and Emc10), has a large lumenal region and a smaller cytosolic region, and has a Transmembrane region formed by Emc4, Emc5 and Emc6 plus the Transmembrane Domains of Emc1 and Emc3. We identified a five-TMH fold centred around Emc3 that resembles the prokaryotic YidC insertase and that delineates a largely hydrophilic client protein pocket. The Transmembrane Domain of Emc4 tilts away from the main Transmembrane region of EMC and is partially mobile. Mutational studies demonstrated that the flexibility of Emc4 and the hydrophilicity of the client pocket are required for EMC function. The EMC structure reveals notable evolutionary conservation with the prokaryotic insertases4,5, suggests that eukaryotic TMH insertion involves a similar mechanism, and provides a framework for detailed understanding of membrane insertion for numerous eukaryotic integral membrane proteins and tail-anchored proteins.