scholarly journals Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

2021 ◽  
Author(s):  
Tobias J Buscham ◽  
Maria A. Eichel-Vogel ◽  
Anna M Steyer ◽  
Olaf Jahn ◽  
Nicola Strenzke ◽  
...  
Keyword(s):  
Early Onset ◽  
Wallerian Degeneration ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Myelin Proteins ◽  
Myelin Protein ◽  
Impulse Propagation ◽  
Functional Relevance

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here we find that expression of the tetraspan-transmembrane protein CMTM5 (Chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and CNS myelin. Genetic disruption of the Cmtm5-gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial Cmtm5-deficiency causes an early-onset progressive axonopathy, which we also observe in global and in tamoxifen-induced oligodendroglial Cmtm5-mutants. Presence of the Wlds mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis.

scholarly journals Cryo-EM structure of human Wntless in complex with Wnt3a

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing Zhong ◽  
Yanyu Zhao ◽  
Fangfei Ye ◽  
Zaiyu Xiao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Multiple Interfaces ◽  
Wnt Proteins ◽  
Binding Partners ◽  
Multiple Binding Sites ◽  
Evolutionarily Conserved ◽  
Multiple Binding ◽  
Hydrophobic Tunnel ◽  
Conserved Core

AbstractWntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

scholarly journals Vaccinia Virus A26 and A27 Proteins Form a Stable Complex Tethered to Mature Virions by Association with the A17 Transmembrane Protein

2008 ◽  
Vol 82 (24) ◽  
pp. 12384-12391 ◽  
Author(s):  
Amanda R. Howard ◽  
Tatiana G. Senkevich ◽  
Bernard Moss
Keyword(s):  
Vaccinia Virus ◽  
Matrix Protein ◽  
Transmembrane Domain ◽  
Noncovalent Complex ◽  
Transmembrane Protein ◽  
Amino Acid Identity ◽  
Noncovalent Interaction ◽  
Terminal Segment ◽  
Stable Complex ◽  
Cowpox Virus

ABSTRACT During vaccinia virus replication, mature virions (MVs) are wrapped with cellular membranes, transported to the periphery, and exported as extracellular virions (EVs) that mediate spread. The A26 protein is unusual in that it is present in MVs but not EVs. This distribution led to a proposal that A26 negatively regulates wrapping. A26 also has roles in the attachment of MVs to the cell surface and incorporation of MVs into proteinaceous A-type inclusions in some orthopoxvirus species. However, A26 lacks a transmembrane domain, and nothing is known regarding how it associates with the MV, regulates incorporation of the MV into inclusions, and possibly prevents EV formation. Here, we provide evidence that A26 forms a disulfide-bonded complex with A27 that is anchored to the MV through a noncovalent interaction with the A17 transmembrane protein. In the absence of A27, A26 was unstable, and only small amounts were detected. The interaction of A26 with A27 depended on a C-terminal segment of A26 with 45% amino acid identity to A27. Deletion of A26 failed to enhance EV formation by vaccinia virus, as had been predicted. Nevertheless, the interaction of A26 and A27 may have functional significance, since each is thought to mediate binding to cells through interaction with laminin and heparan sulfate, respectively. We also found that A26 formed a noncovalent complex with A25, a truncated form of the cowpox virus A-type inclusion matrix protein. The latter association suggests a mechanism for incorporation of virions into A-type inclusions in other orthopoxvirus strains.

ANOREXIA NERVOSA

PEDIATRICS ◽  
1982 ◽  
Vol 70 (4) ◽  
pp. 525-525
Author(s):  
Robert J. Haggerty
Keyword(s):  
Anorexia Nervosa ◽  
Early Onset ◽  
Age Of Onset ◽  
Outcome Studies ◽  
Psychosomatic Disorder ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Follow Up Studies

Anorexia nervosa is a serious psychosomatic disorder which most typically begins between 16 and 18 years of age. Clinicians have often held that early onset (eg, ages 11 to 15) is associated with a better outcome. This paper reviews the long-term outcome studies on anorexia nervosa and concludes that this contention is not supported by available data. The methodologies of seven outcome studies that focus on an early onset population are critiqued, and it is concluded that two methodologies are strong. Because of the increasing prevalence of anorexia nervosa, this once rare disorder can now be more easily investigated, and consequently better follow-up studies, which examine potential prognostic factors including age of onset, should be forthcoming.

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

2021 ◽  
Vol 14 (687) ◽  
pp. eaba0717
Author(s):  
Shunsuke Kataoka ◽  
Priyanka Manandhar ◽  
Judong Lee ◽  
Creg J. Workman ◽  
Hridesh Banerjee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Inhibitory Protein ◽  
Immune Synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

scholarly journals Canine Influenza Virus is Mildly Restricted by Canine Tetherin Protein

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 565
Author(s):  
Yun Zheng ◽  
Xiangqi Hao ◽  
Qingxu Zheng ◽  
Xi Lin ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cellular Damage ◽  
Interferon Response ◽  
Type I ◽  
Canine Influenza Virus ◽  
Immune Factor ◽  
Canine Influenza ◽  
The Impact

Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I transmembrane protein with one transmembrane domain, no signal peptide, and multiple glycosylation and phosphorylation sites. Furthermore, the tissue expression profile of canine tetherin revealed that it was particularly abundant in immune organs. The canine tetherin gene contains an interferon response element sequence that can be regulated and expressed by canine IFN-α. A CCK-8 assay showed that canine tetherin was effective in helping mitigate cellular damage caused by canine influenza virus (CIV) infection. Additionally, we found that the overexpression of canine tetherin inhibited replication of the CIV and that interference with the canine tetherin gene enhanced CIV replication in cells. The impact of canine tetherin on CIV replication was mild. However, these results elucidate the role of the innate immune factor, canine tetherin, during CIV infection for the first time.

scholarly journals Hypoxia Alters the Expression of Dipeptidyl Peptidase 4 and Induces Developmental Remodeling of Human Preadipocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Helena H. Chowdhury ◽  
Jelena Velebit ◽  
Nataša Radić ◽  
Vito Frančič ◽  
Marko Kreft ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transmembrane Protein ◽  
Human Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Hypoxic Conditions ◽  
Human Preadipocytes ◽  
Developmental Remodeling

Dipeptidyl peptidase 4 (DPP4), a transmembrane protein, has been identified in human adipose tissue and is considered to be associated with obesity-related type 2 diabetes. Since adipose tissue is relatively hypoxic in obese participants, we investigated the expression of DPP4 in human preadipocytes (hPA) and adipocytes in hypoxia, during differentiation and upon insulin stimulation. The results show that DPP4 is abundantly expressed in hPA but very sparsely in adipocytes. During differentiationin vitro, the expression of DPP4 in hPA is reduced on the addition of differentiation medium, indicating that this protein can be hPA marker. Long term hypoxia altered the expression of DPP4 in hPA. Inin vitrohypoxic conditions the protease activity of shed DPP4 is reduced; however, in the presence of insulin, the increase in DPP4 expression is potentiated by hypoxia.

scholarly journals Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation

2017 ◽  
Vol 114 (35) ◽  
pp. E7262-E7271 ◽  
Author(s):  
Alexander G. Karabadzhak ◽  
Lisa M. Petti ◽  
Francisco N. Barrera ◽  
Anne P. B. Edwards ◽  
Andrés Moya-Rodríguez ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Receptor Activation ◽  
Bovine Papillomavirus ◽  
Detailed Model ◽  
E5 Protein ◽  
Membrane Modeling ◽  
E5 Oncoprotein ◽  
Β Receptor ◽  
Dynamics Simulations

The dimeric 44-residue E5 protein of bovine papillomavirus is the smallest known naturally occurring oncoprotein. This transmembrane protein binds to the transmembrane domain (TMD) of the platelet-derived growth factor β receptor (PDGFβR), causing dimerization and activation of the receptor. Here, we use Rosetta membrane modeling and all-atom molecular dynamics simulations in a membrane environment to develop a chemically detailed model of the E5 protein/PDGFβR complex. In this model, an active dimer of the PDGFβR TMD is sandwiched between two dimers of the E5 protein. Biochemical experiments showed that the major PDGFβR TMD complex in mouse cells contains two E5 dimers and that binding the PDGFβR TMD to the E5 protein is necessary and sufficient to recruit both E5 dimers into the complex. These results demonstrate how E5 binding induces receptor dimerization and define a molecular mechanism of receptor activation based on specific interactions between TMDs.

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