5obn

NMR solution structure of U11/U12 65K protein's C-terminal RRM domain (381-516)

spinqualitylabelsall models 5obn Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5obn is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RNPC3_HUMAN Isolated growth hormone deficiency type IA. The disease is caused by variants affecting the gene represented in this entry. Function 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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