Defining the roles and interactions of PTB.

Abstract:

:PTB (polypyrimidine tract-binding protein) is an abundant and widely expressed RNA-binding protein with four RRM (RNA recognition motif) domains. PTB is involved in numerous post-transcriptional steps in gene expression in both the nucleus and cytoplasm, but has been best characterized as a regulatory repressor of some ASEs (alternative splicing events), and as an activator of translation driven by IRESs (internal ribosome entry segments). We have used a variety of approaches to characterize the activities of PTB and its molecular interactions with RNA substrates and protein partners. Using splice-sensitive microarrays we found that PTB acts not only as a splicing repressor but also as an activator, and that these two activities are determined by the location at which PTB binds relative to target exons. We have identified minimal splicing repressor and activator domains, and have determined high resolution structures of the second RRM domain of PTB binding to peptide motifs from the co-repressor protein Raver1. Using single-molecule techniques we have determined the stoichiometry of PTB binding to a regulated splicing substrate in whole nuclear extracts. Finally, we have used tethered hydroxyl radical probing to determine the locations on viral IRESs at which each of the four RRM domains bind. We are now combining tethered probing with single molecule analyses to gain a detailed understanding of how PTB interacts with pre-mRNA substrates to effect either repression or activation of splicing.

journal_name

Biochem Soc Trans

authors

Kafasla P,Mickleburgh I,Llorian M,Coelho M,Gooding C,Cherny D,Joshi A,Kotik-Kogan O,Curry S,Eperon IC,Jackson RJ,Smith CW

doi

10.1042/BST20120044

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

815-20

issue

4

eissn

0300-5127

issn

1470-8752

pii

BST20120044

journal_volume

40

pub_type

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