Structural highlights
Disease
LARP7_HUMAN Microcephalic primordial dwarfism, Alazami type. The disease is caused by mutations affecting the gene represented in this entry.
Function
LARP7_HUMAN Negative transcriptional regulator of polymerase II genes, acting by means of the 7SK RNP system. Within the 7SK RNP complex, the positive transcription elongation factor b (P-TEFb) is sequestered in an inactive form, preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation.[1] [2]
Publication Abstract from PubMed
The non-coding RNA 7SK is the scaffold for a small nuclear ribonucleoprotein (7SKsnRNP) which regulates the function of the positive transcription elongation factor P-TEFb in the control of RNA polymerase II elongation in metazoans. The La-related protein LARP7 is a component of the 7SKsnRNP required for stability and function of the RNA. To address the function of LARP7 we determined the crystal structure of its La module, which binds a stretch of uridines at the 3'-end of 7SK. The structure shows that the penultimate uridine is tethered by the two domains, the La-motif and the RNA-recognition motif (RRM1), and reveals that the RRM1 is significantly smaller and more exposed than in the La protein. Sequence analysis suggests that this impacts interaction with 7SK. Binding assays, footprinting and small-angle scattering experiments show that a second RRM domain located at the C-terminus binds the apical loop of the 3' hairpin of 7SK, while the N-terminal domains bind at its foot. Our results suggest that LARP7 uses both its N- and C-terminal domains to stabilize 7SK in a closed structure, which forms by joining conserved sequences at the 5'-end with the foot of the 3' hairpin and has thus functional implications.
Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7.,Uchikawa E, Natchiar KS, Han X, Proux F, Roblin P, Zhang E, Durand A, Klaholz BP, Dock-Bregeon AC Nucleic Acids Res. 2015 Mar 9. pii: gkv173. PMID:25753663[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ He N, Jahchan NS, Hong E, Li Q, Bayfield MA, Maraia RJ, Luo K, Zhou Q. A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. Mol Cell. 2008 Mar 14;29(5):588-99. Epub 2008 Jan 31. PMID:18249148 doi:http://dx.doi.org/S1097-2765(08)00036-1
- ↑ Markert A, Grimm M, Martinez J, Wiesner J, Meyerhans A, Meyuhas O, Sickmann A, Fischer U. The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes. EMBO Rep. 2008 Jun;9(6):569-75. Epub 2008 May 16. PMID:18483487 doi:http://dx.doi.org/embor200872
- ↑ Uchikawa E, Natchiar KS, Han X, Proux F, Roblin P, Zhang E, Durand A, Klaholz BP, Dock-Bregeon AC. Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7. Nucleic Acids Res. 2015 Mar 9. pii: gkv173. PMID:25753663 doi:http://dx.doi.org/10.1093/nar/gkv173
