scholarly journals Does human P-glycoprotein efflux involve transmembrane alpha helix breakage?

2019 ◽  
Author(s):  
Cátia A. Bonito ◽  
Maria-José U. Ferreira ◽  
Ricardo J. Ferreira ◽  
Daniel J. V. A. dos Santos
Keyword(s):  
Recent Article ◽  
Alpha Helix ◽  
Transmembrane Domains ◽  
Lateral Compression ◽  
P Glycoprotein ◽  
Gate Region

AbstractThe occluded conformation suggested in a recent article that revealed a new inward-facing conformation for the human P-glycoprotein may not represent the closing of a gate region but instead an artifact derived from lateral compression in a too small sized nanodisc, used to stabilize the transmembrane domains of the transporter.

PATTERNS OF HYDROPHOBICITY FOUND IN THE FIRST AND SECOND TRANSMEMBRANE DOMAINS OF SOLUTE TRANSPORTERS SUGGEST A POSSIBLE ROLE IN NASCENT PROTEIN ANCHORING AND ORGANIZATION

2011 ◽  
Vol 09 (04) ◽  
pp. 471-488 ◽  
Author(s):  
STEVE HODGKINSON ◽  
WOLFGANG P. KASCHKA
Keyword(s):  
Amino Acids ◽  
Alpha Helix ◽  
Spatial Arrangement ◽  
Transmembrane Domains ◽  
Integral Membrane Proteins ◽  
Challenging Problem ◽  
Functional Protein ◽  
Spatial Organisation ◽  
Diverse Range ◽  
Solute Transporters

Solute transporters (STs) are an important subgroup of integral membrane proteins that facilitate the translocation of a diverse range of solutes such as sugars, amino acids, and neurotransmitters across cell membranes. Sequence analysis indicates that STs possess multiple stretches of hydrophobic-rich amino acids that are organized into the transmembrane domains (TMDs) of the functional protein, but exactly how the correct spatial arrangement of these domains is achieved remains a challenging problem. We hypothesized that perhaps differences in interdomain hydrophobicity might play some role in this process. To test this hypothesis, we generated a heptadic model of the alpha helix and mapped the average hydrophobicities (coaxial) and hydrophobic moments (radial) of 108 TMDs found in 9 different human ST proteins. Our results, taken together with earlier work from other groups, suggest that spatial patterns of hydrophobicity found in TMDs 1 and 2 are consistent with a role for these domains in the initial anchoring of the nascent ST protein to the endoplasmic reticulum (ER), as it emerges from the ribosome complex and perhaps in the subsequent spatial organisation of STs.

scholarly journals Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

2006 ◽  
Vol 50 (9) ◽  
pp. 3102-3110 ◽  
Author(s):  
José M. Pérez-Victoria ◽  
Fernando Cortés-Selva ◽  
Adriana Parodi-Talice ◽  
Boris I. Bavchvarov ◽  
F. Javier Pérez-Victoria ◽  
...  
Keyword(s):  
Active Drug ◽  
Transmembrane Domains ◽  
Drug Efflux ◽  
Binding Domains ◽  
Mammalian Cell Lines ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Leishmania Spp ◽  
Orally Active ◽  
Glycoprotein Inhibitors

ABSTRACT Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-β-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

scholarly journals Data-driven homology modelling of P-glycoprotein in the ATP-bound state indicates flexibility of the transmembrane domains

FEBS Journal ◽  
2009 ◽  
Vol 276 (4) ◽  
pp. 964-972 ◽  
Author(s):  
Thomas Stockner ◽  
Sjoerd J. de Vries ◽  
Alexandre M. J. J. Bonvin ◽  
Gerhard F. Ecker ◽  
Peter Chiba
Keyword(s):  
Homology Modelling ◽  
Bound State ◽  
Transmembrane Domains ◽  
Data Driven ◽  
P Glycoprotein

TMCC3 localizes at the three-way junctions for the proper tubular network of the endoplasmic reticulum

2019 ◽  
Vol 476 (21) ◽  
pp. 3241-3260
Author(s):  
Sindhu Wisesa ◽  
Yasunori Yamamoto ◽  
Toshiaki Sakisaka
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Mammalian Cells ◽  
Coiled Coil ◽  
Transmembrane Domains ◽  
Domain Family ◽  
Coiled Coil Domain ◽  
U2os Cells ◽  
Er Membrane

The tubular network of the endoplasmic reticulum (ER) is formed by connecting ER tubules through three-way junctions. Two classes of the conserved ER membrane proteins, atlastins and lunapark, have been shown to reside at the three-way junctions so far and be involved in the generation and stabilization of the three-way junctions. In this study, we report TMCC3 (transmembrane and coiled-coil domain family 3), a member of the TEX28 family, as another ER membrane protein that resides at the three-way junctions in mammalian cells. When the TEX28 family members were transfected into U2OS cells, TMCC3 specifically localized at the three-way junctions in the peripheral ER. TMCC3 bound to atlastins through the C-terminal transmembrane domains. A TMCC3 mutant lacking the N-terminal coiled-coil domain abolished localization to the three-way junctions, suggesting that TMCC3 localized independently of binding to atlastins. TMCC3 knockdown caused a decrease in the number of three-way junctions and expansion of ER sheets, leading to a reduction of the tubular ER network in U2OS cells. The TMCC3 knockdown phenotype was partially rescued by the overexpression of atlastin-2, suggesting that TMCC3 knockdown would decrease the activity of atlastins. These results indicate that TMCC3 localizes at the three-way junctions for the proper tubular ER network.

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