Sandbox Reserved 939

U11/U12-65K is one of the proteins specific for the minor spliceosome. Most eukaryotic genomes harbor two types of spliceosomal introns, called U2-type and U12-type introns, which are excised by two different spliceosomes. U12-type introns are rare, and only present a small fraction of introns in any given eukaryotic genome. The U12-dependent spliceosome, also called the minor spliceosome, is responsible for the removal of these rare introns. Both spliceosomes consist of five small nuclear ribonucleoprotein particles (snRNPs), which are U1, U2, U4, U5 and U6 for the U2-dependent spliceosome and U11, U12, U4atac, U5 and U6atac for the U12-dependent spliceosome. The protein composition of the two spliceosomes is similar, and so far only seven proteins specific for the minor spliceosome have been identified^[1][2][3]. All seven proteins (called 65K, 59K, 48K, 35K, 31K, 25K and 20K) are components of the U11/U12 di-snRNP^[3] that is responsible for the initial recognition of the U12-type splice sites and bridging of the 5' and 3' ends of the intron.

Structure

Domain structure

The human protein contains two RNA recognition motifs (RRM), one close to the N-terminus (residues 27-102) and another one near the C-terminus (residues 420-503), as well as a proline-rich region (residues 196-233) located between the two RRMs. The C-terminal RRM exhibits higher conservation, and is homologous to the N-terminal RRMs of the U1-A and U2-B" proteins^[4], which are components of the U1 and U2 snRNPs, respectively. The C-terminal RRM binds specifically to a stem-loop structure in the U12 snRNA, whereas the N-terminal half (residues 1-257) of the protein interacts with the U11-59K protein.

Crystal structure of human U11/U12-65K

The structure of the C-terminal RNA recognition motif and an N-terminal extension (residues 380-517) of human U11/U12-65K has been determined by X-ray crystallography^[5].

Disease association

Mutations in the gene encoding the U11/U12-65K protein (RNPC3) were recently shown to cause isolated growth hormone deficiency (IGHD) and pituitary hypoplasia^[6].

References

1. ↑ Will CL, Schneider C, Reed R, Luhrmann R. Identification of both shared and distinct proteins in the major and minor spliceosomes. Science. 1999 Jun 18;284(5422):2003-5. PMID:10373121
2. ↑ Schneider C, Will CL, Makarova OV, Makarov EM, Luhrmann R. Human U4/U6.U5 and U4atac/U6atac.U5 tri-snRNPs exhibit similar protein compositions. Mol Cell Biol. 2002 May;22(10):3219-29. PMID:11971955
3. ↑ ^{3.0 3.1} Will CL, Schneider C, Hossbach M, Urlaub H, Rauhut R, Elbashir S, Tuschl T, Luhrmann R. The human 18S U11/U12 snRNP contains a set of novel proteins not found in the U2-dependent spliceosome. RNA. 2004 Jun;10(6):929-41. PMID:15146077
4. ↑ Benecke H, Luhrmann R, Will CL. The U11/U12 snRNP 65K protein acts as a molecular bridge, binding the U12 snRNA and U11-59K protein. EMBO J. 2005 Sep 7;24(17):3057-69. Epub 2005 Aug 11. PMID:16096647 doi:http://dx.doi.org/7600765
5. ↑ Netter C, Weber G, Benecke H, Wahl MC. Functional stabilization of an RNA recognition motif by a noncanonical N-terminal expansion. RNA. 2009 Jul;15(7):1305-13. Epub 2009 May 15. PMID:19447915 doi:10.1261/rna.1359909
6. ↑ Argente J, Flores R, Gutierrez-Arumi A, Verma B, Martos-Moreno GA, Cusco I, Oghabian A, Chowen JA, Frilander MJ, Perez-Jurado LA. Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. EMBO Mol Med. 2014 Mar;6(3):299-306. doi: 10.1002/emmm.201303573. Epub 2014 Jan, 30. PMID:24480542 doi:http://dx.doi.org/10.1002/emmm.201303573