View source for 5obn


==NMR solution structure of U11/U12 65K protein's C-terminal RRM domain (381-516)==
<StructureSection load='5obn' size='340' side='right'caption='[[5obn]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5obn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OBN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OBN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5obn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5obn OCA], [https://pdbe.org/5obn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5obn RCSB], [https://www.ebi.ac.uk/pdbsum/5obn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5obn ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RNPC3_HUMAN RNPC3_HUMAN] Isolated growth hormone deficiency type IA. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/RNPC3_HUMAN RNPC3_HUMAN] Participates in pre-mRNA U12-dependent splicing, performed by the minor spliceosome which removes U12-type introns. U12-type introns comprises less than 1% of all non-coding sequences. Binds to the 3'-stem-loop of m(7)G-capped U12 snRNA.<ref>PMID:16096647</ref> <ref>PMID:19447915</ref> <ref>PMID:24480542</ref> <ref>PMID:29255062</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mutations in the components of the minor spliceosome underlie several human diseases. A subset of patients with isolated growth hormone deficiency (IGHD) harbor mutations in the RNPC3 gene, which encodes the minor spliceosome-specific U11/U12-65K protein. Although a previous study showed that IGHD patient cells have defects in U12-type intron recognition, the biochemical effects of these mutations on the 65K protein have not been characterized. Here, we show that a proline-to-threonine missense mutation (P474T) and a nonsense mutation (R502X) in the C-terminal RNA recognition motif (C-RRM) of the 65K protein impair the binding of 65K to U12 and U6atac snRNAs. We further show that the nonsense allele is targeted to the nonsense-mediated decay (NMD) pathway, but in an isoform-specific manner, with the nuclear-retained 65K long-3'UTR isoform escaping NMD pathway. In contrast, the missense P474T mutation leads, in addition to the RNA binding defect, to a partial defect in the folding of the C-RRM and reduced stability of the full-length protein, thus reducing the formation of U11/U12 di-snRNP complexes. We propose that both the C-RRM folding defect and NMD-mediated decrease in the levels of the U11/U12-65K protein lead to reduced formation of the U12-type intron recognition complex and missplicing of a subset of minor introns, as reported by Argente et al. (2014), leading to pituitary hypoplasia and a subsequent defect in growth hormone secretion.

Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA.,Norppa AJ, Kauppala TM, Heikkinen HA, Verma B, Iwai H, Frilander MJ RNA. 2017 Dec 18. pii: rna.062844.117. doi: 10.1261/rna.062844.117. PMID:29255062<ref>PMID:29255062</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5obn" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Frilander MJ]]
[[Category: Heikkinen HA]]
[[Category: Iwai H]]
[[Category: Kauppala TM]]
[[Category: Norppa AJ]]
[[Category: Verma B]]