| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The R3H domain is a conserved sequence motif, identified in over 100 proteins, that is thought to be involved in polynucleotide-binding, including DNA, RNA and single-stranded DNA. In this work the 3D structure of the R3H domain from human Smubp-2 was determined by NMR spectroscopy. It is the first 3D structure determination of an R3H domain. The fold presents a small motif, consisting of a three-stranded antiparallel beta-sheet and two alpha-helices, which is related to the structures of the YhhP protein and the C-terminal domain of the translational initiation factor IF3. The similarities are non-trivial, as the amino acid identities are below 10%. Three conserved basic residues cluster on the same face of the R3H domain and could play a role in nucleic acid recognition. An extended hydrophobic area at a different site of the molecular surface could act as a protein-binding site. A strong correlation between conservation of hydrophobic amino acids and side-chain solvent protection indicates that the structure of the Smubp-2 R3H domain is representative of R3H domains in general.
Solution structure of the R3H domain from human Smubp-2.,Liepinsh E, Leonchiks A, Sharipo A, Guignard L, Otting G J Mol Biol. 2003 Feb 7;326(1):217-23. PMID:12547203[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
- ↑ Liepinsh E, Leonchiks A, Sharipo A, Guignard L, Otting G. Solution structure of the R3H domain from human Smubp-2. J Mol Biol. 2003 Feb 7;326(1):217-23. PMID:12547203
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