A cyclophilin functions in pre-mRNA splicing

被引：93

作者：

Horowitz, DS ^{[1
]}

Lee, EJ

Mabon, SA

Misteli, T

机构：

[1] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA

[2] NCI, NIH, Bethesda, MD 20892 USA

来源：

EMBO JOURNAL | 2002年 / 21卷 / 03期

关键词：

cyclophilin; cyclosporin A; hPrp4; hPrp18; pre-mRNA splicing;

D O I：

10.1093/emboj/21.3.470

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report that the cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the cyclophilin is exposed. The cyclophilin inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins.

引用

页码：470 / 480

页数：11

共 38 条

[1]

Ayadi L, 1997, RNA, V3, P197

[2] Functional and structural characterization of the Prp3 binding domain of the yeast Prp4 splicing factor [J].

Ayadi, L ;

Callebaut, I ;

Saguez, C ;

Villa, T ;

Mornon, JP ;

Banroques, J .

JOURNAL OF MOLECULAR BIOLOGY, 1998, 284 (03) :673-687

[3] THE CYCLOPHILIN HOMOLOG NINAA FUNCTIONS AS A CHAPERONE, FORMING A STABLE COMPLEX IN-VIVO WITH ITS PROTEIN TARGET RHODOPSIN [J].

BAKER, EK ;

COLLEY, NJ ;

ZUKER, CS .

EMBO JOURNAL, 1994, 13 (20) :4886-4895

[4] Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells [J].

Braaten, D ;

Luban, J .

EMBO JOURNAL, 2001, 20 (06) :1300-1309

[5]

Burge CB, 1999, RNA WORLD, P525

[6] Inefficient processing impairs release of RNA from the site of transcription [J].

Custódio, N ;

Carmo-Fonseca, M ;

Geraghty, F ;

Pereira, HS ;

Grosveld, F ;

Antoniou, M .

EMBO JOURNAL, 1999, 18 (10) :2855-2866

[7] Active-site residues of cyclophilin A are crucial for its incorporation into human immunodeficiency virus type 1 virions [J].

Dorfman, T ;

Weimann, A ;

Borsetti, A ;

Walsh, CT ;

Gottlinger, HG .

JOURNAL OF VIROLOGY, 1997, 71 (09) :7110-7113

[8]

Galat A, 1998, PEPTIDYL PROLYL CIS

[9] Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid [J].

Gamble, TR ;

Vajdos, FF ;

Yoo, SH ;

Worthylake, DK ;

Houseweart, M ;

Sundquist, WI ;

Hill, CP .

CELL, 1996, 87 (07) :1285-1294

[10]

HIGMAN MA, 1992, J BIOL CHEM, V267, P16430

← 1 2 3 4 →