In silico оценка возможного патогенетического влияния миссенс варианта c.441G>A p.(Met147Ile) гена SLC26A4 на функцию/структуру белка пендрина с применением нейросетевого алгоритма AlfhаFold

В работе впервые проведена in silico оценка возможного патогенетического влияния варианта c.441G>A p.(Met147Ile) гена SLC26A4, имеющего в настоящее время статус -вариант неопределенного значения (US - uncertain significance), на функцию/структуру белка пендрина (SLC26A4), выполненного при помощи нейросетевого алгоритма AlphaFold, предсказывающего пространственную структуру белка, когда подобная структура неизвестна. На основе предсказанной модели третичной структуры пендрина человека, было проведено выравнивание мутантной (p.Met147Ile) и нативной структуры белка с помощью графической программы PyMOL. В результате рассчитанный показатель сходства двух структур RMSD (среднеквадратичное отклонение положения атомов) составил меньше 2 Å, то есть миссенс замена p.(Met147Ile) теоретически не нарушает структурную стабильность белка. Вероятно, патогенетическое влияние мутации происходит на функциональном уровне, поскольку анализируемая замена p.(Met147Ile) находится в критическом участке корового домена (эволюционно консервативный участок α3-спирали TMD), нарушение которого может привести к неправильной транспортировке субстрата или появлению токсичных конформаций в трансмембранной области.

in silico анализ, миссенс-замена, ген SLC26A4, белок пендрин (SLC26A4), система AlfhаFold, Якутия

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