| Structural highlights
Function
PTBP1_HUMAN Plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. Activates exon skipping of its own pre-mRNA during muscle cell differentiation. Binds to the polypyrimidine tract of introns. May promote RNA looping when bound to two separate polypyrimidine tracts in the same pre-mRNA. May promote the binding of U2 snRNP to pre-mRNA. Cooperates with RAVER1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA. Represses the splicing of MAPT/Tau exon 10.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The N-terminal RNA recognition motif domain (RRM1) of polypyrimidine tract binding protein (PTB) forms an additional C-terminal helix alpha3, which docks to one edge of the beta-sheet upon binding to a stem-loop RNA containing a UCUUU pentaloop. Importantly, alpha3 does not contact the RNA. The alpha3 helix therefore represents an allosteric means to regulate the conformation of adjacent domains in PTB upon binding structured RNAs. Here we investigate the process of dynamic adaptation by stem-loop RNA and RRM1 using NMR and MD in order to obtain mechanistic insights on how this allostery is achieved. Relaxation data and NMR structure determination of the free protein show that alpha3 is partially ordered and interacts with the domain transiently. Stem-loop RNA binding quenches fast time scale dynamics and alpha3 becomes ordered, however microsecond dynamics at the protein-RNA interface is observed. MD shows how RRM1 binding to the stem-loop RNA is coupled to the stabilization of the C-terminal helix and helps to transduce differences in RNA loop sequence into changes in alpha3 length and order. IRES assays of full length PTB and a mutant with altered dynamics in the alpha3 region show that this dynamic allostery influences PTB function in cultured HEK293T cells.
N-terminal domain of polypyrimidine-tract binding protein is a dynamic folding platform for adaptive RNA recognition.,Damberger FF, Krepl M, Arora R, Beusch I, Maris C, Dorn G, Sponer J, Ravindranathan S, Allain FH Nucleic Acids Res. 2024 Aug 24:gkae713. doi: 10.1093/nar/gkae713. PMID:39180402[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Markovtsov V, Nikolic JM, Goldman JA, Turck CW, Chou MY, Black DL. Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol Cell Biol. 2000 Oct;20(20):7463-79. PMID:11003644
- ↑ Wang J, Gao QS, Wang Y, Lafyatis R, Stamm S, Andreadis A. Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors. J Neurochem. 2004 Mar;88(5):1078-90. PMID:15009664
- ↑ Lin JC, Tarn WY. Exon selection in alpha-tropomyosin mRNA is regulated by the antagonistic action of RBM4 and PTB. Mol Cell Biol. 2005 Nov;25(22):10111-21. PMID:16260624 doi:http://dx.doi.org/10.1128/MCB.25.22.10111-10121.2005
- ↑ Lin JC, Tarn WY. RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing. J Cell Biol. 2011 May 2;193(3):509-20. doi: 10.1083/jcb.201007131. Epub 2011 Apr , 25. PMID:21518792 doi:http://dx.doi.org/10.1083/jcb.201007131
- ↑ Oberstrass FC, Auweter SD, Erat M, Hargous Y, Henning A, Wenter P, Reymond L, Amir-Ahmady B, Pitsch S, Black DL, Allain FH. Structure of PTB bound to RNA: specific binding and implications for splicing regulation. Science. 2005 Sep 23;309(5743):2054-7. PMID:16179478 doi:http://dx.doi.org/309/5743/2054
- ↑ Damberger FF, Krepl M, Arora R, Beusch I, Maris C, Dorn G, Šponer J, Ravindranathan S, Allain FH. N-terminal domain of polypyrimidine-tract binding protein is a dynamic folding platform for adaptive RNA recognition. Nucleic Acids Res. 2024 Aug 24:gkae713. PMID:39180402 doi:10.1093/nar/gkae713
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