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Book ; Online ; Thesis: Studien zum Transport von Schilddrüsenhormonen durch Membrantransporter der MCT- und LAT-Familie

Kinne, Anita [Verfasser]

2011

Author's details	Anita Kinne
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	German
Publisher	Medizinische Fakultät Charité - Universitätsmedizin Berlin
Publishing place	Berlin
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10.

Johannes, Jörg / Braun, Doreen / Kinne, Anita / Rathmann, Daniel / Köhrle, Josef / Schweizer, Ulrich

Molecular endocrinology (Baltimore, Md.)

2016 Volume 30, Issue 7, Page(s) 796–808

Abstract: Monocarboxylate transporters (MCTs) belong to the SLC16 family within the major facilitator superfamily of transmembrane transporters. MCT8 is a thyroid hormone transporter mutated in the Allan-Herndon-Dudley syndrome, a severe psychomotor retardation ... ...

Abstract	Monocarboxylate transporters (MCTs) belong to the SLC16 family within the major facilitator superfamily of transmembrane transporters. MCT8 is a thyroid hormone transporter mutated in the Allan-Herndon-Dudley syndrome, a severe psychomotor retardation syndrome. MCT10 is closely related to MCT8 and is known as T-type amino acid transporter. Both transporters mediate T3 transport, but although MCT8 also transports rT3 and T4, these compounds are not efficiently transported by MCT10, which, in contrast, transports aromatic amino acids. Based on the 58% amino acid identity within the transmembrane regions among MCT8 and MCT10, we reasoned that substrate specificity may be primarily determined by a small number of amino acid differences between MCT8 and MCT10 along the substrate translocation channel. Inspecting the homology model of MCT8 and a structure-guided alignment between both proteins, we selected 8 amino acid positions and prepared chimeric MCT10 proteins with selected amino acids changed to the corresponding amino acids in MCT8. The MCT10 mutant harboring 8 amino acid substitutions was stably expressed in Madin-Darby canine kidney 1 cells and found to exhibit T4 transport activity. We then successively reduced the number of amino acid substitutions and eventually identified a minimal set of 2-3 amino acid exchanges which were sufficient to allow T4 transport. The resulting MCT10 chimeras exhibited KM values for T4 similar to MCT8 but transported T4 at a slower rate. The acquisition of T4 transport by MCT10 was associated with complete loss of the capacity to transport Phe, when Tyr184 was mutated to Phe.
MeSH term(s)	Amino Acid Transport Systems, Neutral/chemistry ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Amino Acids/chemistry ; Amino Acids/genetics ; Amino Acids/metabolism ; Animals ; Biotinylation ; Blotting, Western ; Cell Line ; Chromatography, Liquid ; Dogs ; Monocarboxylic Acid Transporters/chemistry ; Monocarboxylic Acid Transporters/genetics ; Monocarboxylic Acid Transporters/metabolism ; Mutagenesis, Site-Directed ; Substrate Specificity ; Tandem Mass Spectrometry ; Thyroid Hormones/metabolism ; Triiodothyronine/metabolism ; Xenopus
Chemical Substances	Amino Acid Transport Systems, Neutral ; Amino Acids ; Monocarboxylic Acid Transporters ; Thyroid Hormones ; Triiodothyronine (06LU7C9H1V)
Language	English
Publishing date	2016-05-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	639167-9
ISSN	1944-9917 ; 0888-8809
ISSN (online)	1944-9917
ISSN	0888-8809
DOI	10.1210/me.2016-1037
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Article ; Online: Primary and secondary thyroid hormone transporters.

Kinne, Anita / Schülein, Ralf / Krause, Gerd

Thyroid research

2011 Volume 4 Suppl 1, Page(s) S7

Abstract: Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the ... ...

Abstract	Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the Monocarboxylate transporter 8 (MCT8), which was found to be highly specific for TH transport. However, additional transmembrane transporters are also very important for TH uptake and efflux in different cell types. They transport TH as secondary substrates and include the aromatic amino acid transporting MCT10, the organic anion transporting polypeptides (e.g. OATP1C1, OATP1A2, OPTP1A4) and the large neutral amino acid transporters (LAT1 and LAT2). These TH transporters characteristically possess 12 transmembrane spanners but due to the strong differing sequences between the three transporter families we assume an identical conformation is not very likely. In contrast to the others, the LAT family members form a heterodimer with the escort protein 4F2hc/CD98. A comparison of sequence proportions, locations and types of functional sensitive features for TH transport discovered by mutations, revealed that transport sensitive charged residues occur as conserved amino acids only within each family of the transporter types but not in all putative TH transporters. Based on the lack of highly conserved sensitive charged residues throughout the three transporter families as a common counterpart for the amino acid moiety of the substrates, we conclude that the molecular transport mechanism is likely organized either a) by different molecular determinants in the divergent transporter types or b) the counterparts for the substrates` amino acid moiety at the transporter are not any charged side chains but other proton acceptors or donators. However, positions of transport sensitive residues coincide at transmembrane helix 8 in the TH transporter MCT8, OATP1C1 and another amino acid transporter, the L-cystine and L-glutamate exchanger xCT, which is highly homologous to LAT1 and LAT2. Here we review the data available and compare similarities and differences between these primary and secondary TH transporters regarding sequences, topology, potential structures, trafficking to the plasma membrane, molecular features and locations of transport sensitive functionalities. Thereby, we focus on TH transporters occurring in the blood-brain barrier.
Language	English
Publishing date	2011-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2454440-1
ISSN	1756-6614 ; 1756-6614
ISSN (online)	1756-6614
ISSN	1756-6614
DOI	10.1186/1756-6614-4-S1-S7
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Article ; Online: Structural insights into thyroid hormone transport mechanisms of the L-type amino acid transporter 2.

Hinz, Katrin M / Meyer, Katja / Kinne, Anita / Schülein, Ralf / Köhrle, Josef / Krause, Gerd

Molecular endocrinology (Baltimore, Md.)

2015 Volume 29, Issue 6, Page(s) 933–942

Abstract: Thyroid hormones (THs) are transported across cell membranes by different transmembrane transporter proteins. In previous studies, we showed marked 3,3'-diiodothyronine (3,3'-T2) but moderate T3 uptake by the L-type amino acid transporter 2 (Lat2). We ... ...

Abstract	Thyroid hormones (THs) are transported across cell membranes by different transmembrane transporter proteins. In previous studies, we showed marked 3,3'-diiodothyronine (3,3'-T2) but moderate T3 uptake by the L-type amino acid transporter 2 (Lat2). We have now studied the structure-function relationships of this transporter and TH-like molecules. Our Lat2 homology model is based on 2 crystal structures of the homologous 12-transmembrane helix transporters arginine/agmatine antiporter and amino acid/polyamine/organocation transporter. Model-driven mutagenesis of residues lining an extracellular recognition site and a TH-traversing channel identified 9 sensitive residues. Using Xenopus laevis oocytes as expression system, we found that side chain shortening (N51S, N133S, N248S, and Y130A) expanded the channel and increased 3,3'-T2 transport. Side chain enlargements (T140F, Y130R, and I137M) decreased 3,3'-T2 uptake, indicating channel obstructions. The opposite results with mutations maintaining (F242W) or impairing (F242V) uptake suggest that F242 may have a gating function. Competitive inhibition studies of 14 TH-like compounds revealed that recognition by Lat2 requires amino and carboxylic acid groups. The size of the adjacent hydrophobic group is restricted. Bulky substituents in positions 3 and 5 of the tyrosine ring are allowed. The phenolic ring may be enlarged, provided that the whole molecule is flexible enough to fit into the distinctly shaped TH-traversing channel of Lat2. Taken together, the next Lat2 features were identified 1) TH recognition site; 2) TH-traversing channel in the center of Lat2; and 3) switch site that potentially facilitates intracellular substrate release. Together with identified substrate features, these data help to elucidate the molecular mechanisms and role of Lat2 in T2 transport.
MeSH term(s)	Amino Acid Transport System y+/chemistry ; Amino Acid Transport System y+/genetics ; Amino Acid Transport System y+/metabolism ; Animals ; Biological Transport ; Crystallography, X-Ray ; Fusion Regulatory Protein 1, Light Chains/chemistry ; Fusion Regulatory Protein 1, Light Chains/genetics ; Fusion Regulatory Protein 1, Light Chains/metabolism ; Mice ; Models, Biological ; Mutation/genetics ; Phenylalanine/metabolism ; Structural Homology, Protein ; Substrate Specificity ; Thyroid Hormones/metabolism ; Xenopus laevis
Chemical Substances	Amino Acid Transport System y+ ; Fusion Regulatory Protein 1, Light Chains ; SLC7A8 protein, mouse ; Thyroid Hormones ; Phenylalanine (47E5O17Y3R)
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639167-9
ISSN	1944-9917 ; 0888-8809
ISSN (online)	1944-9917
ISSN	0888-8809
DOI	10.1210/me.2015-1044
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Article ; Online: The tricyclic antidepressant desipramine inhibits T3 import into primary neurons.

Roth, Stephan / Kinne, Anita / Schweizer, Ulrich

Neuroscience letters

2010 Volume 478, Issue 1, Page(s) 5–8

Abstract: Transport of thyroid hormones across the plasma membrane is required for binding to their nuclear receptors. Monocarboxylate transporter 8 (MCT8) is a plasma membrane thyroid hormone transport protein, which has recently gained much attention, since ... ...

Abstract	Transport of thyroid hormones across the plasma membrane is required for binding to their nuclear receptors. Monocarboxylate transporter 8 (MCT8) is a plasma membrane thyroid hormone transport protein, which has recently gained much attention, since mutations in MCT8 are associated with severe mental retardation in patients afflicted with the Allan-Herndon-Dudley syndrome. MCT8 is expressed along the blood-brain-barrier and on central neurons. We have found that desipramine (DMI), a tricyclic antidepressant, acts as an inhibitor of thyroid hormone transport by MCT8. Uptake of 3,5,3'-triiodo-L-thyronine (T(3)) into primary cortical neurons could be blocked with desipramine as well as with the known, but unspecific, inhibitor bromosulphtalein (BSP). T(3) uptake by neurons derived from Mct8-deficient cells was not further decreased by DMI. In a heterologous expression system, both human MCT8 and its close homolog, MCT10, were sensitive to inhibition by DMI. Kinetic experiments demonstrated a non-competitive mode of inhibition. Numerous interactions between thyroid hormones, depressive symptoms, and antidepressant treatments have been reported in the literature. Our findings add to the evidence that antidepressant drugs may affect CNS thyroid hormone function.
MeSH term(s)	Amino Acid Transport Systems, Neutral/antagonists & inhibitors ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Animals ; Antidepressive Agents, Tricyclic/pharmacology ; Biological Transport ; Cells, Cultured ; Cerebral Cortex/drug effects ; Cerebral Cortex/metabolism ; Desipramine/pharmacology ; Dogs ; Humans ; Mice ; Monocarboxylic Acid Transporters/antagonists & inhibitors ; Monocarboxylic Acid Transporters/genetics ; Monocarboxylic Acid Transporters/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Sulfobromophthalein/pharmacology ; Triiodothyronine/metabolism
Chemical Substances	Amino Acid Transport Systems, Neutral ; Antidepressive Agents, Tricyclic ; Monocarboxylic Acid Transporters ; SLC16A10 protein, human ; SLC16A2 protein, human ; Triiodothyronine (06LU7C9H1V) ; Sulfobromophthalein (0C2P5QKL36) ; Desipramine (TG537D343B)
Language	English
Publishing date	2010-06-30
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2010.04.055
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Article ; Online: Primary and secondary thyroid hormone transporters

Kinne Anita / Schülein Ralf / Krause Gerd

Thyroid Research , Vol 4, Iss Suppl 1, p S

2011 Volume 7

Abstract: Abstract Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in ... ...

Abstract	Abstract Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the Monocarboxylate transporter 8 (MCT8), which was found to be highly specific for TH transport. However, additional transmembrane transporters are also very important for TH uptake and efflux in different cell types. They transport TH as secondary substrates and include the aromatic amino acid transporting MCT10, the organic anion transporting polypeptides (e.g. OATP1C1, OATP1A2, OPTP1A4) and the large neutral amino acid transporters (LAT1 and LAT2). These TH transporters characteristically possess 12 transmembrane spanners but due to the strong differing sequences between the three transporter families we assume an identical conformation is not very likely. In contrast to the others, the LAT family members form a heterodimer with the escort protein 4F2hc/CD98. A comparison of sequence proportions, locations and types of functional sensitive features for TH transport discovered by mutations, revealed that transport sensitive charged residues occur as conserved amino acids only within each family of the transporter types but not in all putative TH transporters. Based on the lack of highly conserved sensitive charged residues throughout the three transporter families as a common counterpart for the amino acid moiety of the substrates, we conclude that the molecular transport mechanism is likely organized either a) by different molecular determinants in the divergent transporter types or b) the counterparts for the substrates` amino acid moiety at the transporter are not any charged side chains but other proton acceptors or donators. However, positions of transport sensitive residues coincide at transmembrane helix 8 in the TH transporter MCT8, OATP1C1 and another amino acid transporter, the L-cystine and L-glutamate exchanger xCT, which is highly homologous to LAT1 and LAT2. Here we review the data available and compare similarities and differences between these primary and secondary TH transporters regarding sequences, topology, potential structures, trafficking to the plasma membrane, molecular features and locations of transport sensitive functionalities. Thereby, we focus on TH transporters occurring in the blood-brain barrier.
Keywords	Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	500
Language	English
Publishing date	2011-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3'-Diiodothyronine across the Plasma Membrane.

Kinne, Anita / Wittner, Melanie / Wirth, Eva K / Hinz, Katrin M / Schülein, Ralf / Köhrle, Josef / Krause, Gerd

European thyroid journal

2015 Volume 4, Issue Suppl 1, Page(s) 42–50

Abstract: Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, for example by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) ... ...

Abstract	Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, for example by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. The specificity of Lat2 for thyroid hormones and their metabolites and its role in their transport was not fully clear. This fact motivated us to establish a cell system to elucidate the uptake of thyroid hormones and their metabolites by mouse Lat2. The coinjection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased level of 3,3'-diiodo-L-thyronine (3,3'-T2) and to some extent also enhanced T3 transport. To gain insight into properties of thyroid hormones and their metabolites transported by Lat2, we inhibited 3,3'-T2 uptake by various iodothyronine derivatives. T1 and T2 derivatives as well as 2-aminobicyclo-[2, 2,1]-heptane-2-carboxylic acid strongly competed with 3,3'-T2 uptake. In addition, we performed T2 uptake measurements with the thyroid hormone-specific transporter MCT8. For both Lat2 and MCT8, Km values in a low micromolar range were calculated. We demonstrated that oocytes are a suitable system for thyroid hormone transport studies mediated by Lat2. Our data indicates that Lat2 compared to other thyroid hormone transporters prefers 3,3'-T2 as the substrate. Thus, Lat2 might contribute to the availability of thyroid hormone by importing and/or exporting 3,3'-T2, which is generated either by T3 inactivation or by rapid deiodinase 1-mediated rT3 degradation.
Language	English
Publishing date	2015-05-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2659767-6
ISSN	2235-0802 ; 2235-0640
ISSN (online)	2235-0802
ISSN	2235-0640
DOI	10.1159/000381542
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Article ; Online: Insights into molecular properties of the human monocarboxylate transporter 8 by combining functional with structural information.

Kleinau, Gunnar / Schweizer, Ulrich / Kinne, Anita / Köhrle, Josef / Grüters, Annette / Krude, Heiko / Biebermann, Heike

Thyroid research

2011 Volume 4 Suppl 1, Page(s) S4

Abstract: Background: The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known ... ...

Abstract	Background: The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties. Methods: We designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity. Results: We found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8. Conclusions: Naturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure-function relationships at MCT8 which may bear broader relevance for other members of the MCT family. This includes decoding of the complete set of transport-sensitive residue positions and description of structural re-arrangements during transport.
Language	English
Publishing date	2011-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2454440-1
ISSN	1756-6614 ; 1756-6614
ISSN (online)	1756-6614
ISSN	1756-6614
DOI	10.1186/1756-6614-4-S1-S4
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Article ; Online: Surface translocation and tri-iodothyronine uptake of mutant MCT8 proteins are cell type-dependent.

Kinne, Anita / Roth, Stephan / Biebermann, Heike / Köhrle, Josef / Grüters, Annette / Schweizer, Ulrich

Journal of molecular endocrinology

2009 Volume 43, Issue 6, Page(s) 263–271

Abstract: Mutations in the gene encoding the thyroid hormone transporter, monocarboxylate transporter 8 (MCT8), underlie severe mental retardation. We wanted to understand the functional consequences of a series of missense mutations in MCT8 in order to identify ... ...

Abstract	Mutations in the gene encoding the thyroid hormone transporter, monocarboxylate transporter 8 (MCT8), underlie severe mental retardation. We wanted to understand the functional consequences of a series of missense mutations in MCT8 in order to identify therapeutic options for affected patients. We established cell lines stably expressing 12 MCT8 variants in JEG1 and MDCK1 cells. The cell lines were characterized according to MCT8 mRNA and protein expression, tri-iodothyronine (T(3)) transport activity, substrate K(M) characteristics, surface expression, and responsiveness to T(3) preincubation and chemical chaperones. Functional activities of ins235V and L568P MCT8 mutants depend on the cell type in which they are expressed. These mutants and R271H exhibited considerable transport activity when present at the cell surface as verified by surface biotinylation and kinetic analysis. Most mutants, however, were inactive in T(3) transport even when present at the cell surface (e.g. S194F, A224V, DeltaF230, L512P). Preincubation of G558D with T(3) increased T(3) uptake in MDCK1 cells to a small, but significant, extent. Chemical chaperones were ineffective. The finding that the cell type determines surface expression and T(3) transport activities of missense mutants in MCT8 may be important to understand phenotypic variability among carriers of different mutations. In particular, the clinical observation that the severity of derangements of thyroid hormone levels does not correlate with mental impairments of the patients may be based on different residual activity of mutant MCT8 in different cell types.
MeSH term(s)	Animals ; Blotting, Northern ; Blotting, Western ; Cell Line ; Dogs ; HeLa Cells ; Humans ; Monocarboxylic Acid Transporters/genetics ; Monocarboxylic Acid Transporters/metabolism ; Mutation, Missense ; Triiodothyronine/metabolism
Chemical Substances	Monocarboxylic Acid Transporters ; SLC16A2 protein, human ; Triiodothyronine (06LU7C9H1V)
Language	English
Publishing date	2009-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1677/JME-09-0043
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Article ; Online: Insights into molecular properties of the human monocarboxylate transporter 8 by combining functional with structural information

Kleinau Gunnar / Schweizer Ulrich / Kinne Anita / Köhrle Josef / Grüters Annette / Krude Heiko / Biebermann Heike

Thyroid Research , Vol 4, Iss Suppl 1, p S

2011 Volume 4

Abstract: Abstract Background The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation ...

Abstract	Abstract Background The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties. Methods We designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity. Results We found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8. Conclusions Naturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure-function relationships at MCT8 which may bear broader relevance for other members of the MCT family. This includes decoding of the complete set of transport-sensitive residue positions and description of structural re-arrangements during transport.
Keywords	Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	500
Language	English
Publishing date	2011-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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