Взаимодействие протимозина альфа с адаптером убиквитин-лигазы белком Keap1 тема диссертации и автореферата по ВАК РФ 02.00.10, кандидат химических наук Мельников, Сергей Викторович

• Мельников, Сергей Викторович
• кандидат химических наук
• 2008

Оглавление диссертации кандидат химических наук Мельников, Сергей Викторович

СПИСОК УСЛОВНЫХ ОБОЗНАЧЕНИЙ.

ВВЕДЕНИЕ.

1. ВНУТРИКЛЕТОЧНЫЕ ФУНКЦИИ ПРОТИМОЗИНА а обзор литературы).

1.1. Протимозин а (РгоТа) - многофункциональный белок позвоночных животных.

1.2. Структура РгоТа.

1.2.1. Аминокислотный состав и первичная структура РгоТа.

1.2.2. Пространственная структура РгоТа.

1.2.3. Посттрансляционные модификации РгоТа.

1.3. Количество РгоТа в клетках различных тканей.

1.4. Внутриклеточная локализация РгоТа.

1.4.1. РгоТа содержит сигнал ядерной локализации.

1.4.2. РгоТа - ядерный белок, непрерывно мигрирующий между ядром и цитоплазмой.

1.4.3. В ядре клетки РгоТа сосредоточен в гранулообразных доменах

1.5. Внутриклеточные функции РгоТа.

1.5.1. РгоТа ускоряет прохождение клетки по циклу деления.

1.5.2. РгоТа является гистон-связывающим белком in vitro и в лизатах клеток и деконденсирует хроматин клеток при сверхпродукции.

1.5.3. РгоТа специфически усиливает экспрессию некоторых генов

1.5.4. РгоТа подавляет апоптотический путь клеточной смерти и расщепляется в процессе апоптоза.

1.5.5. РгоТа взаимодействует с белком Keapl.

2. ФУНКЦИОНАЛЬНЫЕ ПОСЛЕДСТВИЯ ВЗАИМОДЕЙСВТИЯ ПРОТИМОЗИНА а С БЕЛКОМ КЕАР1 (результаты и обсуждение)

2.1. РгоТа - стабильный белок, не подверженный деградации 26S протеасомой.

2.2. РгоТа не подвержен убиквитинированию.

2.3. РгоТа не оказывает влияния на степень убиквитинирования транскрипционного фактора Nrf2.

2.4. ProTa устойчив к Keapl-зависимому экспорту из ядра.

2.5. Устойчивость РгоТа к Keapl-зависимому экспорту из ядра обусловлена сигналом ядерной локализации в структуре РгоТа.

Введение диссертации (часть автореферата) на тему «Взаимодействие протимозина альфа с адаптером убиквитин-лигазы белком Keap1»

В природе, помимо свернутых в глобулы и фибриллы белков, существует малоисследованная группа полипептидов, лишенных стабильных элементов вторичной и третичной структуры. Эти белки, называемые несвернутыми (natively unfolded) или природно неупорядоченными (intrinsically disordered), существуют в клетке в виде переходящих друг в друга конформеров неупорядоченного клубка, но это не мешает им выполнять важные биологические функции как в процессах нормальной жизнедеятельности клетки, так и в процессах адаптации к различным воздействиям на клетку окружающей среды.Данная работа посвящена исследованию свойств несвернутого белка протимозина а. Этот белок обладает целым рядом уникальных свойств, необычных для большинства белковых молекул. Исследования последних лет показали, что протимозин а обладает множеством биологических функций и для некоторых из них был установлен механизм. В частности, в нашей лаборатории было показано, что протимозин а является молекулярным партнером белка Keapl, который, в свою очередь, был охарактеризован как адаптер убиквитин-лигазы, направляющий белки на деградацию. В данной работе наши усилия были направлены на выявление возможных последствий для протимозина а от его взаимодействия с белком Keapl.

Заключение диссертации по теме «Биоорганическая химия», Мельников, Сергей Викторович

1. Протимозин а человека, являясь молекулярным партнером адаптера убиквитин-лигазы белка Keapl, не подвергается убиквитинированию и деградации протеасомой.2. Протимозин а сохраняет свою ядерную локализацию в клетках человека в присутствии белка Keapl.3. Keapl способен экспортировать из ядра в цитоплазму мутанты протимозина а с ослабленным сигналом ядерной локализации. Этот результат доказывает, что белки Keapl и протимозин а взаимодействуют in vivo, и что наличие сильного сигнала ядерной локализации в структуре протимозина а является причиной устойчивости протимозина а дикого типа к перераспределению белком Keapl из ядра в цитоплазму.

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