Поиск ферментов, контролирующих ядерно-цитоплазматическое распределение белка YB-1 в клетках млекопитающих тема диссертации и автореферата по ВАК РФ 03.00.03, кандидат биологических наук Сорокин, Алексей Витальевич

• Сорокин, Алексей Витальевич
• кандидат биологических наук
• 2007

Оглавление диссертации кандидат биологических наук Сорокин, Алексей Витальевич

ВВЕДЕНИЕ.

ОБЗОР ЛИТЕРАТУРЫ.

I. Ядерно-цитоплазматический транспорт белков.

1. Введение.

2. Кап-зависимый ядерно-цитоплазматический транспорт белков.

2.1. Сигналы ядерно-цитоплазматического транспорта и транспортные факторы

2.1.1. Сигналы ядерной локализации и кариоферины-а.

2.1.2. Сигналы ядерной локализации и импортины.

2.1.3. Сигналы ядерного экспорта и экспортины.

2.2. Строение ядерного порового комплекса, нуклеопорины.

2.3. Модель Кап-зависимого транспорта.

2.3.1. Кап, регуляторы Кап.

2.3.2. Посадка комплекса кариоферин-а/импортин-р1/сЖ8-белок на №С.

2.3.3. Прохождение комплекса кариоферин-а/импортин-Р1/сЫЬ8-белок через центральный канал ядерной поры.

2.3.4. Разборка комплекса кариоферин-а/импортин-р1/с№Л>-белок.

2.3.5. Перемещение белков из ядра в цитоплазму.

2.3.6. Яап-связывающие белки.

2.4. Транспорт белков внутренней ядерной мембраны.

3. Кап-независимый ядерно-цитоплазматический транспорт белков.

4. Регуляция ядерно-цитоплазматического транспорта.

4.1. Регуляция транспорта за счёт модуляции взаимодействий импортина/экспортина с сигналом ЫЬБ/ЫЕБ субстрата.

4.1.1. Маскирование сигналов ЫЬБ/ЫЕБ субстрата от узнавания импортином/экспортином.

4.1.1.1. Внутримолекулярное маскирование сигналов ЖБ/ЫЕБ субстрата.

4.1.1.2. Межмолекулярное маскирование сигналов ЫЬБ/ЫЕБ субстрата.

4.1.2. Регуляция транспорта за счёт усиления связывания импотрина/экспортина с сигналом ЫЬБ/ЫЕБ субстрата.

4.1.3. Регуляция транспорта за счёт удержания в цитоплазме или в ядре.

4.1.4. Регуляция транспорта за счёт котранспортировки и изменения субстрат-связывающих свойств кариоферина.

4.2. Регуляция транспорта за счёт изменения состава импортинов и экспортинов

4.3. Регуляция транспорта за счёт изменения состава нуклеопоринов.

II. Мультифункциональный ядерно-цитоплазматический белок УВ-1.

1. История открытия белков семейства УВ-1.

2. Структурно-функциональная организация УВ-1.

2.1. Домен холодового шока.

2.2. С-концевой домен.

3. Функции УВ-1 в ядре.

3.1. Участие УВ-1 в регуляции транскрипции.

3.2. Участие УВ-1 в репликации и репарации ДНК.

3.3. Участие УВ-1 в сплайсинге.

3.4. Участие УВ-1 в разборке ядрышек.

4. Функции УВ-1 в цитоплазме.

4.1. Участие YB-1 в трансляции.

4.2. Участие YB-1 в упаковке мРНК.

4.3. Участие YB-1 в регуляции стабильности мРНК.

4.4. Участие YB-1 в локализации мРНК.

4.5. Участие белков семейства YB-1 в процессинге мРНК.

5. Ядерно-цитоплазматический транспорт YB-1.

5.1. Сигнальные последовательности в молекуле YB-1.

5.2. Механизм ядерно-цитоплазматического транспорта YB-1.

5.3. Возможные механизмы регуляции ядерно-цитоплазматического транспорта YB-1.

5.3.1. Регуляция транспорта YB-1 за счёт взаимодействия с мРНК.

5.3.2. Тромбин стимулирует переход YB-1 в ядро в эндотелиальных клетках

5.3.3. Переход YB-1 в ядро в комплексе с другими белками.

5.3.4. Фосфорилирование YB-1 может влиять на его ядерно-цитоплазматическое распределение.

6. УВ-1ирак.

Введение диссертации (часть автореферата) на тему «Поиск ферментов, контролирующих ядерно-цитоплазматическое распределение белка YB-1 в клетках млекопитающих»

Пространственное разделение синтеза мРНК и трансляции позволило эукариотам достичь совершенной регуляции экспрессии генов. Такое разграничение двух основополагающих клеточных процессов привело к формированию очень сложного механизма транспортировки макромолекул через ядерную мембрану. Упрощённо, ядерно-цитоплазматический транспорт сводится к тому, что ядерные белки импортируются в ядро, а РНК экспортируется в цитоплазму. На самом деле, транспорт и белков и РНК через ядерную мембрану может быть двунаправленным, и, в последние годы, список белков, постоянно перемещающихся между цитоплазмой и ядром, существенно расширился. Создаётся впечатление, что именно такие ядерно-цитоплазматические «белки-челноки» являются ключевыми звеньями в передаче информации между двумя основными компартментами клетки. Первые свидетельства, указывающие на возможность перемещения белков между цитоплазмой и ядром, были получены в 1950-х годах (Goldstein, 1958). Тем не менее, потребовалось ещё около 30 лет пока был идентифицирован первый «белок-челнок» - нуклеолин (Borer et al., 1989). К настоящему времени список белков, перемещающихся между цитоплазмой и ядром, включает транспортные рецепторы и адаптеры (Gorlich and Kutay, 1999; Nakielny and Dreyfiiss, 1999), рецепторы стероидных гормонов (Hache et al., 1999), факторы транскрипции (Cartwright and Helin, 2000), регуляторы клеточного цикла (Pines, 1999; Yang and Kornbluth, 1999) и множество РНК-связывающих белков (Nakielny and Dreyfiiss, 1999; Shyu and Wilkinson, 2000).

Y-бокс связывающий белок 1 (YB-1) - это внутриклеточный ядерно-цитоплазматический белок млекопитающих с молекулярной массой около 36 кДа. YB-1 - белок мультифункциональный, его участие в широком спектре внутриклеточных процессов объясняется прежде всего достаточно уникальной способностью взаимодействовать как с ДНК, так и с РНК, а также связываться с большим числом других клеточных белков (Kohno et al., 2003). Взаимодействуя с определенными регуляторными последовательностями в ДНК, в том числе с участками, содержащими Y-боксы в промоторах и энхансерах генов, YB-1 позитивно или негативно влияет на экспрессию ряда важнейших клеточных генов (Kohno et al., 2003). Среди них гены факторов роста, гены, участвующие в делении 6 клеток, апоптозе, иммунном ответе, развитии множественной лекарственной устойчивости, стрессовых ответах, регуляции опухолевого роста, а также ряд вирусных генов. YB-1 обладает повышенным сродством к участкам ДНК с поврежденной вторичной структурой и способствует процессу их репарации, а ускоряя обмен комплементарных нуклеотидных последовательностей в двойных спиралях, он, как предполагается, может участвовать в рекомбинации ДНК (Ise et al, 1999; Skabkin et al., 2001). Имеются данные о вовлечении YB-1 и в процесс репликации ДНК (Levenson et al., 2000). Одним словом, YB-1, по-видимому, играет роль практически во всех ДНК-зависимых процессах. В ходе синтеза мРНК, YB-1 связывается с их предшественниками ещё на хромосомах и потом сопровождает молекулы мРНК на протяжении всей их жизни (Kohno et al., 2003). В клеточном ядре белок участвует в альтернативном сплайсинге предшественников мРНК (Chansky et al., 2001). В цитоплазме подавляющая часть YB-1 может находиться в ассоциации с транслируемыми и нетранслируемыми мРНК, определяя их функциональную активность, стабильность, а также локализацию трансляционно активных мРНК на актиновом скелете (Davydova et al., 1997; Evdokimova et al., 2001; Ruzanov et al., 1999).

Участие YB-1 в таком широком спектре клеточных процессов позволило прийти к выводу, что характер действия YB-1 на клеточные процессы зависит не только от его содержания в клетке, но также и от его распределения между ядром и цитоплазмой, которое должно строго регулироваться. Если общие механизмы ядерно-цитоплазматического транспорта белков изучены достаточно детально, то информация о транспортировке YB-1 скудна и никогда не обобщалась. В связи с этим, нам показалось очень важным и интересным проанализировать известные механизмы регуляции ядерно-цитоплазматического транспорта белков, включая данные об YB-1 по этой теме.

ОБЗОР ЛИТЕРАТУРЫ

ЯДЕРНО-ЦИТОПЛАЗМАТИЧЕСКИЙ ТРАНСПОРТ БЕЛКОВ: РЕГУЛЯЦИЯ

РАСПРЕДЕЛЕНИЯ YB-1 В КЛЕТКЕ

I, Ядерно-цитоплазматический транспорт белков 1. Введение

В эукариотических клетках цитоплазма и ядро сообщаются через ядерные поровые комплексы, встроенные в ядерную мембрану. Ядерный поровый комплекс -NPC (nuclear pore complex), состоящий из -30 различных белков нуклеопоринов (nucleoporin) (Rout and Aiíchison, 2000), образует канал и регулирует ядерно-цитоплазматический транспорт различных типов РНК (Franke and Scheer, 1974), мембранных белков (рецепторов) (King et ai, 2006) и растворимых белков (S unth a ra 1 i ng am and Wente, 2003).

А Б В ii

NPC

Рисунок 1. Упрощённая модель транспорта через ядерную мембрану. (А) Схематичное изображение ядерного норового комплекса (NPC). Обозначения: ЯМ - ядерная мембрана, ЦФ -цитоплазматическая фибрилла, ЯФ - ядерная фибрилла. «FG-поверхность» - образована FG-нуклеопоринами (подробно рассмотрены в главе 2.2. раздела I «Обзора литературы»). Считается, что именно за счёт взаимодействий с FG-нуклеопоринами осуществляется активный транспорт белков через ядерный поровый комплекс. Селективный фильтр - представляет собой сеть из несвернутых гидрофобных полипептидных цепей нуклеопоринов, выстилающих центральный канал NPC. (Б) Ионы и маленькие нейтральные белки способны проходить через селективный фильтр порового комплекса за счёт диффузии. (В) Большие молекулы или комплексы проникают через NPC только в составе транспортных комплексов.

Ядерный поровый комплекс - это большой транспортёр, пронизывающий ядерную мембрану. Ионы и маленькие нейтральные белки, не связывающиеся с нуклеопоринами, проникают через ядерный поровый комплекс за счёт диффузии (Gorlich and Kutay, 1999). В этом случае они проходят через туннель диаметром 8-10 нм и длиной около 45 нм (Keminer and Peters, 1999; Paine et al, 1975) (рисунок 1Б). Если молекулы связываются с нуклеопоринами, диаметр туннеля увеличивается до 40 нм (Pante and Капп, 2002) и транспортировка идёт намного быстрее (рисунок 1В) (Ribbeck and Gorlich, 2001; Siebrasse and Peters, 2002). Селективный фильтр для малых бежов представляет собой сеть из несвернутых гидрофобных полипептидных цепей нуклеопоринов, выстилающих центральный канал NPC (рисунок 1Б). Тем не менее, не смотря на сравнительно большой диаметр туннеля, некоторые, даже маленькие белки (меньше 20-30 кДа), такие как гистоны, проходят через NPC только с посредниками (Breeuwer and Goldfarb, 1990). Основным является транспорт при помощи посредника Ran (Ran-зависимый транспорт). Этот вид транспорта достаточно хорошо изучен. Основной отличительной его чертой является гидролиз GTP, катализируемый Ran. В транспорте, помимо Ran, принимают участие и другие консервативные транспортные факторы.

2. Ran-зависимый ядерно-цитоплазматический транспорт белков

Импорт/экспорт большинства белков, в том числе мембранных, рибосомных субчастиц и некоторых типов РНК происходит при помощи большого, эволюционно консервативного семейства транспортных факторов - кариоферинов-Р (karyopherin-Р). Большинство кариоферинов-Р осуществляют или ядерный импорт и называются импортинами, или ядерный экспорт и называются экспортинами; лишь некоторые из них принимают участие как в экспорте, так и в импорте. Большинство кариоферинов-Р напрямую взаимодействует со своими белками-субстратами, но иногда и через адаптерный белок. Самым изученным адаптерным белком является эволюционно консервативный белок кариоферин-а (kaiyopherin-а), другое название - импортин-a (importin-a). Импортины связываются с сигналом ядерной локализации - NLS (nuclear localization signal) - в транспортируемом белке и перемещают субстрат в ядро. Экспортины связываются с сигналом ядерного экспорта - NES (nuclear export sequence) - в транспортируемом белке и обеспечивают его транспортировку в цитоплазму. Помимо перечисленных, в транспорте в ядро и из ядра участвует дополнительно целый набор транспортных белков. Одним из ключевых белков среди них является GTP-аза Ran. Упрощённая модель Ran-зависимого ядерного транспорта схематически представлена на рисунке

2. Роль Ran в транспорте более подробно будет описана ниже (смотри главу 2.3.1. раздела I «Обзора литературы»).

Рисунок 2, Упрощённая модель Ran-ззвисимого ядерно-цнтоплазматического транспорта белков. (А) Транспорт в ядро. Импорт белков с сигналом ядерной локализации (NLS) осуществляется гетеродимером кар иоферин-а/им порти н -р ] (обозначены а и р). Транспорт белков опосредованный участием только импортинов-p на схеме не показан. (Б) Транспорт из ядра. Большая часть экспорта белков с сигналом ядерного экспорта (NES) осуществляется экспортином Crml (обозначен ехр).

Заключение диссертации по теме «Молекулярная биология», Сорокин, Алексей Витальевич

выводы

1. Выделена и идентифицирована протеаза, вызывающая расщепление YB-1 на два фрагмента. Этой протеазой оказалась 20S протеасома.

2. 20S протеасома расщепляет YB-1 перед Gly-220.

3. Расщепление YB-1 20S протеасомой осуществляется по Ub- и АТР-независимому механизму.

4. Расщеплению подвергается только свободный, не связанный с мРНК YB-1.

5. Расщепление YB-1 протеасомой в клетке происходит в ответ на ДНК-повреждающий стресс.

6. Ядерная локализация укороченного YB-1 коррелирует с активацией защитных механизмов клетки в ответ на обработку терапевтическими препаратами.

7. Фосфорилирование YB-1 киназой Akt не оказывает влияния на его распределение между ядром и цитоплазмой в клетках NIH3T3.

8. Показано, что YB-1, фосфорилированный киназой Akt, хуже взаимодействует с кэп-структурой мРНК и проявляет меньшую активность в ингибировании кэп-зависимой трансляции.

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348. Правильный путь таков: усвой то, что сделали твои предшественники, и иди дальше.1. Лев Николаевич Толстой1. P.S.

349. Очень признателен моим бывшим студентам, ныне самостоятельным исследователям: Сергею Гурьянову и Анастасии Селютиной за помощь, поддержку, дискуссии и желание работать. Надеюсь, их работа также будет интересно и успешно развиваться.

350. Я очень признателен Евгении Викторовне Серебровой за помощь в написании статей, автореферата и диссертационной работы.

351. Благодарю также всех сотрудников Института бежа РАН, с которыми я работал и общался.