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Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure
MÁ. Corral-Rodríguez, M. Stuiver, G. Abascal-Palacios, T. Diercks, I. Oyenarte, J. Ereño-Orbea, AI. de Opakua, FJ. Blanco, JA. Encinar, V. Spiwok, H. Terashima, A. Accardi, D. Müller, LA. Martínez-Cruz,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25184538
DOI
10.1042/bj20140409
Knihovny.cz E-zdroje
- MeSH
- cykliny chemie genetika metabolismus MeSH
- cystathionin-beta-synthasa chemie genetika metabolismus MeSH
- konformace proteinů MeSH
- krystalizace MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutace genetika MeSH
- nukleotidy chemie metabolismus MeSH
- sekundární struktura proteinů MeSH
- sekvence aminokyselin MeSH
- vazebná místa fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recent studies suggest CNNM2 (cyclin M2) to be part of the long-sought basolateral Mg2+ extruder at the renal distal convoluted tubule, or its regulator. In the present study, we explore structural features and ligand-binding capacities of the Bateman module of CNNM2 (residues 429-584), an intracellular domain structurally equivalent to the region involved in Mg2+ handling by the bacterial Mg2+ transporter MgtE, and AMP binding by the Mg2+ efflux protein CorC. Additionally, we studied the structural impact of the pathogenic mutation T568I located in this region. Our crystal structures reveal that nucleotides such as AMP, ADP or ATP bind at only one of the two cavities present in CNNM2429-584. Mg2+ favours ATP binding by alleviating the otherwise negative charge repulsion existing between acidic residues and the polyphosphate group of ATP. In crystals CNNM2429-584 forms parallel dimers, commonly referred to as CBS (cystathionine β-synthase) modules. Interestingly, nucleotide binding triggers a conformational change in the CBS module from a twisted towards a flat disc-like structure that mostly affects the structural elements connecting the Bateman module with the transmembrane region. We furthermore show that the T568I mutation, which causes dominant hypomagnesaemia, mimics the structural effect induced by nucleotide binding. The results of the present study suggest that the T568I mutation exerts its pathogenic effect in humans by constraining the conformational equilibrium of the CBS module of CNNM2, which becomes 'locked' in its flat form.
Citace poskytuje Crossref.org
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- $a Corral-Rodríguez, María Ángeles $u *Structural Biology Unit, Center for Cooperative Research in Bioscience (CIC bioGUNE), Technology Park of Bizkaia, 48160 Bizkaia, Spain.
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- $a Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure / $c MÁ. Corral-Rodríguez, M. Stuiver, G. Abascal-Palacios, T. Diercks, I. Oyenarte, J. Ereño-Orbea, AI. de Opakua, FJ. Blanco, JA. Encinar, V. Spiwok, H. Terashima, A. Accardi, D. Müller, LA. Martínez-Cruz,
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- $a Recent studies suggest CNNM2 (cyclin M2) to be part of the long-sought basolateral Mg2+ extruder at the renal distal convoluted tubule, or its regulator. In the present study, we explore structural features and ligand-binding capacities of the Bateman module of CNNM2 (residues 429-584), an intracellular domain structurally equivalent to the region involved in Mg2+ handling by the bacterial Mg2+ transporter MgtE, and AMP binding by the Mg2+ efflux protein CorC. Additionally, we studied the structural impact of the pathogenic mutation T568I located in this region. Our crystal structures reveal that nucleotides such as AMP, ADP or ATP bind at only one of the two cavities present in CNNM2429-584. Mg2+ favours ATP binding by alleviating the otherwise negative charge repulsion existing between acidic residues and the polyphosphate group of ATP. In crystals CNNM2429-584 forms parallel dimers, commonly referred to as CBS (cystathionine β-synthase) modules. Interestingly, nucleotide binding triggers a conformational change in the CBS module from a twisted towards a flat disc-like structure that mostly affects the structural elements connecting the Bateman module with the transmembrane region. We furthermore show that the T568I mutation, which causes dominant hypomagnesaemia, mimics the structural effect induced by nucleotide binding. The results of the present study suggest that the T568I mutation exerts its pathogenic effect in humans by constraining the conformational equilibrium of the CBS module of CNNM2, which becomes 'locked' in its flat form.
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