EF-hand like Region in the N-terminus of Anoctamin 1 Modulates Channel Activity by Ca²⁺ and Voltage
Experimental Neurobiology
; : 658-669, 2019.
Article
ي En
| WPRIM
| ID: wpr-785791
المكتبة المسؤولة:
WPRO
ABSTRACT
Anoctamin1 (ANO1) also known as TMEM16A is a transmembrane protein that functions as a Ca²⁺ activated chloride channel. Recently, the structure determination of a fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase by X-ray crystallography and a mouse ANO1 by cryo-electron microscopy has provided the insight in molecular architecture underlying phospholipid scrambling and Ca²⁺ binding. Because the Ca²⁺ binding motif is embedded inside channel protein according to defined structure, it is still unclear how intracellular Ca²⁺ moves to its deep binding pocket effectively. Here we show that EF-hand like region containing multiple acidic amino acids at the N-terminus of ANO1 is a putative site regulating the activity of ANO1 by Ca²⁺ and voltage. The EF-hand like region of ANO1 is highly homologous to the canonical EF hand loop in calmodulin that contains acidic residues in key Ca²⁺-coordinating positions in the canonical EF hand. Indeed, deletion and Ala-substituted mutation of this region resulted in a significant reduction in the response to Ca²⁺ and changes in its key biophysical properties evoked by voltage pulses. Furthermore, only ANO1 and ANO2, and not the other TMEM16 isoforms, contain the EF-hand like region and are activated by Ca²⁺. Moreover, the molecular modeling analysis supports that EF-hand like region could play a key role during Ca²⁺ transfer. Therefore, these findings suggest that EF-hand like region in ANO1 coordinates with Ca²⁺ and modulate the activation by Ca²⁺ and voltage.
Key words
النص الكامل:
1
الفهرس:
WPRIM
الموضوع الرئيسي:
Calmodulin
/
Models, Molecular
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Calcium
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Mutagenesis
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Crystallography, X-Ray
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Chloride Channels
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Protein Isoforms
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Cryoelectron Microscopy
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EF Hand Motifs
/
Amino Acids, Acidic
نوع الدراسة:
Prognostic_studies
المحددات:
Animals
اللغة:
En
مجلة:
Experimental Neurobiology
السنة:
2019
نوع:
Article