Molecular features of the L-type amino acid transporter 2 determine different import and export profiles for thyroid hormones and amino acids

Hinz, Katrin Manuela; Neef, Dominik; Rutz, Claudia; Furkert, Jens; Köhrle, Josef; Schülein, Ralf; Krause, Gerd

doi:10.1016/j.mce.2017.01.024

Cited by 13 publications

(19 citation statements)

References 40 publications

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“…SLC7A8 also transports thyroid hormones (TH) ( Zevenbergen et al, 2015 ; Hinz et al, 2017 ) as well as the dopamine precursor L-DOPA ( Gomes and Soares-da-Silva, 2002 ; Pinho et al, 2004 ). Even though hypothyroidism causes hearing loss characterized by alterations in cochlear development ( Peeters et al, 2015 ) and L-DOPA showed a protective role for cochlea during aging ( Murillo-Cuesta et al, 2010 ), Slc7a8 −/− mice showed neither hypothyroidism ( Braun et al, 2011 ) nor alterations in L-DOPA plasma levels (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

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Murillo-Cuesta

et al. 2018

eLife

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Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations.

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Section: Discussionmentioning

confidence: 99%

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Guarch

Font-Llitjós

Murillo-Cuesta

et al. 2018

eLife

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“…Furthermore, and because structure determination of mammalian transporters is highly challenging, homology models of mammalian transporters based on structures of bacterial homologs are of great interest and help towards the understanding of transport function and the identification of new inhibitors and substrates. In recent years, homology modeling combined with structure-function studies or structure-based ligand discovery were reported for human and mammalian SLC7 family members, e.g., for the l -amino acid transporter-1 (LAT1; SLC7A5) [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ] and -2 (LAT2; SLC7A8) [ 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

İlgü

Jeckelmann

Colas

et al. 2018

IJMS

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Abstract:The L-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatographybased thermostability assay was used to determine the melting temperatures (T m s) of the purified AdiC variants in the absence and presence of the selected ligands L-arginine (Arg), agmatine, L-arginine methyl ester, and L-arginine amide. The resulting T m s indicated stabilization of AdiC variants upon ligand binding, in which T m s and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member L-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for L-amino acid substrates to LATs from the SLC7 family.

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“…Although we have made progress and showed previously that Xenopus laevis oocytes are a robust system investigating the TH transport by murine LAT2 [28], direct efflux studies of T2 for LAT3 and selected variants in oocytes and in stably transfected HEK293 cells lines, could not provide evidence of significant TH export by LAT3 (Hinz et al unpublished data).…”

Section: No Mutual Influence Of Lat3 and Lat2mentioning

confidence: 96%

“…In fact leucine efflux but no T2 export by LAT2 was observed in oocytes. In essence, the traversing channel of LAT2 contains distinct molecular determinants that are responsible for a bidirectional amino acid transport but allowing only unidirectional import of particular THs that have been confirmed for LAT2 by mutagenesis [28].…”

Section: Molecular Determinants In Lat2 Responsible For Th Transportmentioning

confidence: 99%

Molecular Mechanisms of Thyroid Hormone Transport by l-Type Amino Acid Transporter

Krause

Hinz

2019

Exp Clin Endocrinol Diabetes

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Thyroid hormones (TH) pass through the plasma membrane into the target cells via transporter proteins. Thyroid hormone transporters that have been identified until now belong to two different solute carrier (SLC) subfamilies i) the major facilitator superfamily (MFS) and ii) the amino acid polyamine-organocation (APC) superfamily. Both are comprised by 12 transmembrane helices, however with different structural topology. The TH transporter MCT8, MCT10 and OATP1C1 are members of the MSF. The l-type amino acid transporters (LATs) are transporting neutral amino acids across the membrane. Two LAT subtypes, LAT1 and LAT2 are members of the APC superfamily, need the escort protein 4F2hc and facilitate uptake but no efflux of TH-subtypes. Homology models of LAT2 that are based on crystal structures of APC transporters guided mutagenesis, revealed molecular structure-function determinants for recognition and transition for import and export of TH-subtypes. The recently solved cryo-EM structure of LAT1 confirmed the structural input. Two other LAT subtypes, LAT3 and LAT4 are members of the MFS. From previous observed negative effect of LAT3 and LAT4 on 3,3’-T2 uptake by LAT1 and LAT2 it was indirectly concluded that LAT3 might export 3,3’-T2. There are still open questions that need to be addressed in order to fully understand the molecular recognition pattern and traversing mechanism of import and export of particular TH-subtypes by LAT1 and LAT2. Moreover, clarification is needed whether LAT3 and LAT4 are exporting TH. Recent new data could not verify the initial hypothesis of TH export by LAT3. Therefore, further investigations are necessary to explain the negative effect of LAT3 on the TH import by LAT2.

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Molecular features of the L-type amino acid transporter 2 determine different import and export profiles for thyroid hormones and amino acids

Cited by 13 publications

References 40 publications

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

Molecular Mechanisms of Thyroid Hormone Transport by l-Type Amino Acid Transporter

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