Функциональная роль неканонических белковых факторов р50 и РТВ в инициации трансляции у млекопитающих тема диссертации и автореферата по ВАК РФ 02.00.10, кандидат химических наук Писарев, Андрей Владимирович

• Писарев, Андрей Владимирович
• кандидат химических наук
• 2003

Оглавление диссертации кандидат химических наук Писарев, Андрей Владимирович

Список сокращений.

Введение.

Обзор литературы

Глава 1. Инициация трансляции у эукариот.

1.1 Механизмы инициации трансляции

1.1.1 Сканирующая модель.

1.1.2 Внутренняя инициация трансляции.

1.2 Канонические факторы инициации трансляции у эукариот.

1.2.1 Факторы, участвующие в образовании 4 8S предынициаторного комплекса eIF2. eIF3. elFl. elFIA. eIF4F. eIF4A. eIF4B. eIF4H.

1.2.2 Факторы, участвующие в образовании 80S комплекса eIF5. eIF5B.

1.3 Неканонические транс-действующие факторы в инициации трансляции. р50.22* гяРНП Е1/Е2 и К.

La аутоантиген.

1.4 Общая модель инициации трансляции у эукариот.

Глава 2. Метод тоупринта в изучении сборки инициаторного комплекса из индивидуальных компонентов.

Результаты и обсуждение

Р50 в инициации трансляции.

1. р50 влияет на связывание 40S рибосомной субчастицы с инициаторным кодоном в сборке 4 8S предынициаторного комплекса из очищенных компонентов in vitro.

2. р50 способен стимулировать образование аберрантного

4 8S комплекса на 5'-конце мРНК.51"

3. Способность р50 стимулировать образование 48S предынициаторного комплекса из очищенных компонентов при низких отношениях р50/мРНК не является универсальным свойством мРНК-связывающих белков.

4. р50 связывается с сахаро-фосфатным остовом мРНК, проявляя предпочтение к последовательностям, содержащим полностью неспаренные нуклеотидные основания.

5. Связывание всего нескольких молекул р50 на молекулу |3-глобиновой мРНК достаточно для стимуляции образования

4 8S предынициаторного комплекса.

6. р50- "менеджер" мРНК-белковых взаимодействий в мРНП млекопитающих.

РТВ- активный участник инициации трансляции на IRES-элементе РНК вируса энцефаломиокардита.

1. РТВ значительно усиливает сборку 48S инициаторного комплекса на РНК ВЭМК из очищенных компонентов in vitro.

2. РТВ проявляет свойства РНК-шаперона.7Q

3. Функция РТВ в IRES-опосредованной инициации трансляции на РНК ряда пикорнавирусов специфична, но не распространяется на все пикорнавирусы.

Материалы и методы

1. Реактивы и материалы.

2 . Плазмидные конструкции.

Ш^Ч 3. Генноинженерные манипуляции.

4. Получение РНК-транскриптов.

5. Трансляция в лизате ретикулоцитов кролика.

6. Реконструкция инициаторных комплексов из очищенных компонентов.

6.1. Выделение рибосомных субчастиц и факторов инициации.

6.2. Аминоацилирование инициаторной тРНК.866.3. Собственно сборка инициаторных комплексов.

6.4. Тоупринт.

7. Центрифугирование комплексов в сахарозном градиенте.

8. Зондирование вторичной структуры мРНК.

Wf^ 9. Иммуноблоттинг-анализ.

10. Ультрафиолетовые сшивки.

11. Количественная обработка результатов.

Выводы.

Введение диссертации (часть автореферата) на тему «Функциональная роль неканонических белковых факторов р50 и РТВ в инициации трансляции у млекопитающих»

В последнее время наблюдается значительный подъём интереса к вопросам регуляции трансляции у млекопитающих. Следует подчеркнуть, что основная регуляция трансляции происходит на стадии инициации. Исследование механизмов инициации трансляции очень актуально на сегодняшний день, так как они точно установлены лишь для простых матриц с короткими и слабоструктурированными 5-НТО и ряда вирусов с ^Ев-зависимой инициацией трансляции.

Безусловно, одним из наиболее перспективных методов в изучении инициации трансляции является реконструкция инициирующих комплексов из очищенных и охарактеризованных компонентов. Его сочетание с техникой тоупринта, применяемой для визуализации комплексов, позволяет убедиться не только в их наличии, но и в "правильности" положения рибосомы на стартовом А1Ю-кодоне (при седиментации в сахарозном градиенте нельзя установить "правильность" комплекса, так как метод позволяет определить лишь коэффициент седиментации). По интенсивности сигнала тоупринта в сравнении с суммарной интенсивностью сигналов в дорожке можно оценивать эффективность сборки инициаторного комплекса. А точно известный набор используемых в сборке факторов дает возможность исследовать механизмы инициации трансляции. Метод реконструкции инициирующих комплексов помимо перечисленных преимуществ ещё и совершенно незаменим при исследовании трансляционного аппарата млекопитающих, поскольку в данном случае использование генетических методов крайне затруднено.

Помимо канонических факторов инициации трансляции, для активности ряда матриц в трансляции необходимы дополнительные белковые факторы, которые регулируют клеточную активность в развитии клетки, делении и апоптозе. Такие неканонические факторы инициации трансляции специфичны в трансляции на определённой стадии клеточного цикла, специфичны для клеток тех или иных тканей, а также отвечают на характерный стресс. Есть лишь общие соображения, касающиеся функциональной роли таких белков в клетке при трансляции, механизм же их действия доподлинно не известен. Многообразие и загадочность поведения в трансляции ставят по важности исследования неканонических факторов инициации трансляции в один ряд с каноническими.

По направленности действия в инициации трансляции есть специфические и общие неканонические белковые факторы. Например, РАВР и р50 связываются с большинством или даже со всеми видами мРНК и в целом контролируют белковый синтез. Р50 является наиболее широко представленным белком и неактивных, и активных полисомальных глобиновых мРНП, хотя последние содержат его в два раза меньше в расчёте на молекулу РНК. Переходы мРНК из неактивного в активное состояние и обратно сопровождаются изменением содержания р50 в составе мРНП.

РТВ, Ьа-аутоантиген, ипг, поли(С)-связывающие белки РСВР1 и РСВР2, ИпКМРК и другие, в отличие от р50, являются специфическими неканоническими белковыми факторами, и их функциональная роль в инициации трансляции проявляется лишь для ряда определённых матриц. РТВ, в частности, требуется для образования 48Э комплекса с 1КЕ8-элементами РНК ряда пикорнавирусов й с клеточной мРНК АраМ, продукт которой вовлечён в регуляцию клеточного апоптоза.

Обладая навыками реконструкции инициирующих комплексов из очищенных и охарактеризованных компонентов в сочетании с техникой тоупринта, мы поставили своей целью в данной работе исследовать по одному примеру неканонического фактора того и другого класса (р50 и РТВ) и выявить их функциональную роль и механизм действия в инициации трансляции у млекопитающих.

Обзор литературы.

Заключение диссертации по теме «Биоорганическая химия», Писарев, Андрей Владимирович

Выводы

1. На основании результатов химического зондирования показано, что р50 связывается с мРНК по сахаро-фосфатному остову, предпочитая участки с полностью неспаренными нуклеотидными основаниями.

2. При низких концентрациях р50 активирует, а при высоких- ингибирует сборку 48S предынициаторного комплекса из очищенных компонентов in vitro.

3. Максимальная стимуляция сборки 48S предынициаторного комплекса соответствует связыванию 6-8 молекул р50 на молекулу р-глобиновой мРНК.

4. р50 стимулирует сборку 48S комплекса на стадии связывания 40S субчастицы с 5'-концом матрицы и, по-видимому, не оказывает влияние на процесс сканирования.

5. При низких концентрациях р50 эффективно конкурирует с факторами инициации трансляции elF2 и elF4F за неспецифические места связывания, проявляя существенно меньшую конкуренцию за функциональные для них участки взаимодействия.

6. РТВ значительно активирует сборку 48S предынициаторного комплекса из очищенных компонентов in vitro на РНК ВЭМК и практически не оказывает влияния на аналогичную сборку с другим представителем пикорнавирусов, PW-1.

7. Методом тоупринта и УФ-сшивок показано влияние РТВ на характер взаимодействия IRES-элемента РНК ВЭМК с одним из основных факторов инициации трансляции elF4G.

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