| Structural highlights
Disease
SMBP2_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]
Function
SMBP2_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 PubMed
The 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
- ↑ Guenther UP, Handoko L, Laggerbauer B, Jablonka S, Chari A, Alzheimer M, Ohmer J, Plottner O, Gehring N, Sickmann A, von Au K, Schuelke M, Fischer U. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1). Hum Mol Genet. 2009 Apr 1;18(7):1288-300. doi: 10.1093/hmg/ddp028. Epub 2009 Jan , 20. PMID:19158098 doi:10.1093/hmg/ddp028
- ↑ Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, Bertini E, Leonhardt-Horti H, Muntoni F, Ouvrier R, Pfeufer A, Rossi R, Van Maldergem L, Wilmshurst JM, Wienker TF, Sendtner M, Rudnik-Schoneborn S, Zerres K, Hubner C. Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet. 2001 Sep;29(1):75-7. PMID:11528396 doi:10.1038/ng703
- ↑ Grohmann K, Varon R, Stolz P, Schuelke M, Janetzki C, Bertini E, Bushby K, Muntoni F, Ouvrier R, Van Maldergem L, Goemans NM, Lochmuller H, Eichholz S, Adams C, Bosch F, Grattan-Smith P, Navarro C, Neitzel H, Polster T, Topaloglu H, Steglich C, Guenther UP, Zerres K, Rudnik-Schoneborn S, Hubner C. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol. 2003 Dec;54(6):719-24. PMID:14681881 doi:10.1002/ana.10755
- ↑ Maystadt I, Zarhrate M, Landrieu P, Boespflug-Tanguy O, Sukno S, Collignon P, Melki J, Verellen-Dumoulin C, Munnich A, Viollet L. Allelic heterogeneity of SMARD1 at the IGHMBP2 locus. Hum Mutat. 2004 May;23(5):525-6. PMID:15108294 doi:10.1002/humu.9241
- ↑ Tachi N, Kikuchi S, Kozuka N, Nogami A. A new mutation of IGHMBP2 gene in spinal muscular atrophy with respiratory distress type 1. Pediatr Neurol. 2005 Apr;32(4):288-90. PMID:15797190 doi:10.1016/j.pediatrneurol.2004.11.003
- ↑ Guenther UP, Varon R, Schlicke M, Dutrannoy V, Volk A, Hubner C, von Au K, Schuelke M. Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis. Hum Mutat. 2007 Aug;28(8):808-15. PMID:17431882 doi:10.1002/humu.20525
- ↑ Guenther UP, Handoko L, Varon R, Stephani U, Tsao CY, Mendell JR, Lutzkendorf S, Hubner C, von Au K, Jablonka S, Dittmar G, Heinemann U, Schuetz A, Schuelke M. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. J Mol Med (Berl). 2009 Jan;87(1):31-41. doi: 10.1007/s00109-008-0402-7. Epub 2008, Sep 18. PMID:18802676 doi:10.1007/s00109-008-0402-7
- ↑ Guenther UP, Handoko L, Laggerbauer B, Jablonka S, Chari A, Alzheimer M, Ohmer J, Plottner O, Gehring N, Sickmann A, von Au K, Schuelke M, Fischer U. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1). Hum Mol Genet. 2009 Apr 1;18(7):1288-300. doi: 10.1093/hmg/ddp028. Epub 2009 Jan , 20. PMID:19158098 doi:10.1093/hmg/ddp028
- ↑ de Planell-Saguer M, Schroeder DG, Rodicio MC, Cox GA, Mourelatos Z. Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Hum Mol Genet. 2009 Jun 15;18(12):2115-26. doi: 10.1093/hmg/ddp134. Epub 2009 Mar, 19. PMID:19299493 doi:10.1093/hmg/ddp134
- ↑ Jaudzems K, Jia X, Yagi H, Zhulenkovs D, Graham B, Otting G, Liepinsh E. Structural Basis for 5'-End-Specific Recognition of Single-Stranded DNA by the R3H Domain from Human Smubp-2. J Mol Biol. 2012 Sep 18. pii: S0022-2836(12)00760-7. doi:, 10.1016/j.jmb.2012.09.010. PMID:22999958 doi:http://dx.doi.org/10.1016/j.jmb.2012.09.010
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