2lrr
Solution structure of the R3H domain from human Smubp-2 in complex with 2'-deoxyguanosine-5'-monophosphate
Structural highlights
DiseaseSMBP2_HUMAN Defects in IGHMBP2 are the cause of distal hereditary motor neuronopathy type 6 (HMN6) [MIM:604320; also known as spinal muscular atrophy distal autosomal recessive 1 (DSMA1) or spinal muscular atrophy with respiratory distress 1 (SMARD1). Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The most prominent symptoms of HMN6 are severe respiratory distress resulting from diaphragmatic paralysis with eventration shown on chest x-ray and predominant involvement of the upper limbs and distal muscles.[1] [2] [3] [4] [5] [6] [7] FunctionSMBP2_HUMAN 5' to 3' helicase that unwinds RNA and DNA duplices in an ATP-dependent reaction. Acts as a transcription regulator. Required for the transcriptional activation of the flounder liver-type antifreeze protein gene. Exhibits strong binding specificity to the enhancer element B of the flounder antifreeze protein gene intron. Binds to the insulin II gene RIPE3B enhancer region. May be involved in translation (By similarity). DNA-binding protein specific to 5'-phosphorylated single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region. Preferentially binds to the 5'-GGGCT-3' motif. Interacts with tRNA-Tyr. Stimulates the transcription of the human neurotropic virus JCV.[8] [9] Publication Abstract from PubMedThe R3H domain is a conserved sequence motif in nucleic acid binding proteins. Previously, we reported the solution structure of the R3H domain and identified a putative nucleic acid binding site composed of three conserved basic residues [Liepinsh, E., Leonchiks, A., Sharipo, A., Guignard, L. & Otting, G. (2003). Solution structure of the R3H domain from human Smubp-2. J. Mol. Biol.326, 217-223]. Here, we determine the binding affinities of mononucleotides and dinucleotides for the R3H domain from human Smubp-2 (Smubp2-R3H) and map their binding sites on the protein's surface. Although the binding affinities show up to 260-fold selectivity between different nucleotides, their binding sites and conformations seem very similar. Further, we report the NMR structure of the Smubp2-R3H in complex with deoxyguanosine 5'-monophosphate (dGMP) mimicking the 5'-end of single-stranded DNA. Pseudocontact shifts from a paramagnetic lanthanide tag attached to residue 731 in the mutant A731C confirmed that binding of dGMP brings a loop of the protein into closer proximity. The structure provides the first structural insight into single-stranded nucleic acid recognition by the R3H domain and shows that the R3H domain specifically binds the phosphorylated 5'-end through electrostatic interactions with the two conserved arginines and stacking interactions with the highly conserved histidine. Structural Basis for 5'-End-Specific Recognition of Single-Stranded DNA by the R3H Domain from Human Smubp-2.,Jaudzems K, Jia X, Yagi H, Zhulenkovs D, Graham B, Otting G, Liepinsh E J Mol Biol. 2012 Sep 18. pii: S0022-2836(12)00760-7. doi:, 10.1016/j.jmb.2012.09.010. PMID:22999958[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
