A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1

Stehantsev, Pavlo; Stetsenko, Artem; Nemchinova, Mariia; Aduri, Nanda G.; Marrink, Siewert J.; Gati, Cornelius; Guskov, Albert

doi:10.1016/j.csbj.2021.09.015

Cited by 12 publications

(15 citation statements)

References 87 publications

(108 reference statements)

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“…In addition, the neutral amino acid exchanger (ASCT1 or SLC1A4) has been shown by loss-of-function studies to contribute to glycine homeostasis in the brain [ 17 ]. Recent studies, however, demonstrated that glycine itself is not a substrate of ASCT1 [ 18 ], suggesting that the effect of ASCT1 deficiency is most likely indirect.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Eulenburg

Hülsmann

2022

IJMS

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In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).

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Section: Introductionmentioning

confidence: 99%

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Eulenburg

Hülsmann

2022

IJMS

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“…Structural research on the SLC1A family has revealed the architectures and transport mechanisms of the archaeal homologs (Glt ph and Glt tk ) [18][19][20][21][22][23][24][25] and four eukaryotic transporters (thermostabilized EAAT1, EAAT3, ASCT1, and ASCT2) [26][27][28][29][30][31][32] . SLC1A transporters are assembled into a trimer, with each protomer consisting of scaffold and transport domains to adopt a unique alternating access model, termed the "elevator-type mechanism" 20,33 .…”

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confidence: 99%

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

et al. 2022

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Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2.

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“…3C), demonstrating a dominant‐negative impact of SLC1A4 L86_M88dup on SLC1A4 WT N‐glycosylation. Notably, the SLC1A4 TMH2 domain that contains residues L86‐R87‐M88 is not known to contain a glycosylation site, as glycosylation is thought to be limited to an extracellular loop present in the TM4 domain located over 100 amino acids C‐terminal to these residues 10 . However, within the trimeric SLC1A4 structure, residues L86‐R87‐M88 directly interact with the TM4 domain of adjacent SLC1A4 monomers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

Pujol‐Giménez

Mirzaa

Blue

et al. 2023

Ann Clin Transl Neurol

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SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine.

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A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1

Abstract: Graphical abstract

Cited by 12 publications

References 87 publications

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

Dominant‐negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

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