Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis / 神经科学通报·英文版
Neuroscience Bulletin
; (6): 57-68, 2023.
Article
em En
| WPRIM
| ID: wpr-971536
Biblioteca responsável:
WPRO
ABSTRACT
PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
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Assunto principal:
Fosfatos
/
Membrana Celular
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Mutação de Sentido Incorreto
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Proteínas Cotransportadoras de Sódio-Fosfato Tipo III
Limite:
Humans
Idioma:
En
Revista:
Neuroscience Bulletin
Ano de publicação:
2023
Tipo de documento:
Article