Unstructured linker regions play a role in the differential splicing activities of paralogous RNA binding proteins PTBP1 and PTBP2

被引：1

作者：

Truong, Anthony ^{[1
,5
]}

Barton, Michael ^{[2
]}

Tran, Uyenphuong ^{[1
]}

Mellody, Montana ^{[1
]}

Berger, Devon ^{[3
]}

Madory, Dean ^{[4
,6
]}

Hitch, Elizabeth ^{[3
,7
]}

Jibrael, Basma ^{[1
,8
]}

Nikolaidis, Nikolas ^{[3
]}

Luchko, Tyler ^{[2
]}

Keppetipola, Niroshika ^{[1
]}

机构：

[1] Calif State Univ Fullerton, Dept Chem & Biochem, Fullerton, CA 92835 USA

[2] Calif State Univ Northridge, Dept Phys & Astron, Northridge, CA 91330 USA

[3] Calif State Univ Fullerton, Dept Biol Sci, Fullerton, CA USA

[4] Santa Ana Coll, Dept Biol Sci, Santa Ana, CA USA

[5] Southern Calif Coll Optometry, 2575 Yorba Linda Blvd, Fullerton, CA 92831 USA

[6] Calif Univ Sci & Med, 1501 Violet St, Colton, CA 92324 USA

[7] Univ Minnesota, Off Equ & Divers, 420 Delaware St SE,MMC 94, Minneapolis, MN USA

[8] Crown Biosci, 16550 W Bernardo Dr Bldg 5,Suite 525, San Diego, CA 92127 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2024年 / 300卷 / 03期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

MOLECULAR-DYNAMICS; SOLVENT; COMPLEX; REPRESSION; GENERATION; EQUATIONS; INCLUSION; MODEL; TOOL;

D O I：

10.1016/j.jbc.2024.105733

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：

RNA Binding Proteins regulate, in part, alternative premRNA splicing and, in turn, gene expression patterns. Polypyrimidine tract binding proteins PTBP1 and PTBP2 are paralogous RNA binding proteins sharing 74% amino acid sequence identity. Both proteins contain four structured RNArecognition motifs (RRMs) connected by linker regions and an N-terminal region. Despite their similarities, the paralogs have distinct tissue-specific expression patterns and can regulate discrete sets of target exons. How two highly structurally similar proteins can exert different splicing outcomes is not well understood. Previous studies revealed that PTBP2 is posttranslationally phosphorylated in the unstructured N-terminal, Linker 1, and Linker 2 regions that share less sequence identity with PTBP1 signifying a role for these regions in dictating the paralog's distinct splicing activities. To this end, we conducted bioinformatics analysis to determine the evolutionary conservation of RRMs versus linker regions in PTBP1 and PTBP2 across species. To determine the role of PTBP2 unstructured regions in splicing activity, we created hybrid PTBP1-PTBP2 constructs that had counterpart PTBP1 regions swapped to an otherwise PTBP2 protein and assayed on differentially regulated exons. We also conducted molecular dynamics studies to investigate how negative charges introduced by phosphorylation in PTBP2 unstructured regions can alter their physical properties. Collectively, results from our studies reveal an important role for PTBP2 unstructured regions and suggest a role for phosphorylation in the differential splicing activities of the paralogs on certain regulated exons.

引用

页数：12