References

medgen

Медицинская генетика

Medical Genetics

2073-7998

Publishing House «Genius Media» LLC

10.25557/2073-7998.2022.06.37-48

medgen-2185

Research Article

ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ

ORIGINAL RESEARCH

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

In silico assessment of the possible pathogenetic effect of the missense variant c.441G>A p.(Met147Ile) of the SLC26A4 gene on the function/structure of the pendrin protein using the AlfhаFold neural network algorithm

Пшенникова

В. Г.

Pshennikova

V. G.

psennikovavera@mail.ru

Романов

Г. П.

Romanov

G. P.

noemail@neicon.ru

Кларов

Л. А.

Klarov

L. A.

noemail@neicon.ru

Барашков

Н. А.

Barashkov

N. A.

noemail@neicon.ru

ФГБНУ «Якутский научный центр комплексных медицинских проблем»РоссияYakut Scientific Center for Complex Medical ProblemsRussian Federation

ФГБНУ «Якутский научный центр комплексных медицинских проблем»; ФГАОУ ВО «Северо-Восточный федеральный университет им. М.К. Аммосова»РоссияYakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal UniversityRussian Federation

2022

09122022

2163748

2022

Пшенникова В.Г., Романов Г.П., Кларов Л.А., Барашков Н.А.

Pshennikova V.G., Romanov G.P., Klarov L.A., Barashkov N.A.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.medgen-journal.ru/jour/article/view/2185

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 this work, for the first time, an in silico evaluation of the possible pathogenic effect of the c.441G>A p.(Met147Ile) variant of uncertain significance of the SLC26A4 gene on the function/structure of the pendrin (SLC26A4) protein was performed using the AlphaFold neural network algorithm, which predicts the spatial structure of the protein when such a structure is unknown. Based on the predicted model of the human pendrin tertiary structure, the alignment of the mutant (p.Met147Ile) and native protein structures was carried out using the PyMOL graphics program. As a result, the calculated similarity index of the two structures RMSD (root-mean-square deviation of atomic positions) was less than 2 Å, which indicates that the missense p.(Met147Ile) substitution theoretically does not violate the structural stability of the protein. Probably, the pathogenic effect of the mutation occurs at the functional level, since the analyzed p.(Met147Ile) is located in a critical region of the core domain (an evolutionarily conserved α3-helix region of the TMD), the disruption of which can lead to incorrect substrate transport or the appearance of toxic conformations in the transmembrane region.

in silico анализмиссенс-заменаген SLC26A4белок пендрин (SLC26A4)система AlfhаFoldЯкутия

in silico analysismissense variantSLC26A4 genependrin protein (SLC26A4)AlfhaFold systemYakutia

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The authors declare that there are no conflicts of interest present.