tailieunhanh - Báo cáo khoa học: New insights into Fragile X syndrome Relating genotype to phenotype at the molecular level

Lack of functional Fragile X mental retardation protein (FMRP) is the pri-mary cause of the Fragile-mental retardation syndrome in humans. In most cases, the disease results from transcriptional silencing of fragile mental retardation gene 1, fmr1, which encodes FMRP. However, a single mis-sense mutation (I304N) in the second KH domain of FMRP gives rise to a particularly severe case of Fragile X syndrome. | iFEBS Journal New insights into Fragile X syndrome Relating genotype to phenotype at the molecular level Irina Pozdnyakova1 and Lynne Regan1 2 1 Department of Molecular Biophysics and Biochemistry Yale University New Haven CT USA 2 Department of Chemistry Yale University New Haven CT USA Keywords Drosophila Fragile X related protein Fragile X syndrome KH domains NMR stability Correspondence L. Regan Department of Molecular Biophysics and Biochemistry Yale University PO Box 208114 New Haven CT 06520-8114 USA E-mail Received 6 October 2004 revised 30 November 2004 accepted 13 December 2004 doi Lack of functional Fragile X mental retardation protein FMRP is the primary cause of the Fragile-mental retardation syndrome in humans. In most cases the disease results from transcriptional silencing of fragile mental retardation gene 1 fmrl which encodes FMRP. However a single missense mutation I304N in the second KH domain of FMRP gives rise to a particularly severe case of Fragile X syndrome. A Drosophila homolog of FMRP has been identified Drosophila Fragile X related protein dFXRP . The corresponding missense mutation in dFXRP the I307N has pronounced effects on the in vivo activity of the protein. The effect of the point mutation on the structure and function of FMRP is unclear and published data are contradictory. No in vitro structural or stability studies have been performed on dFXRP. Here we show that a construct that contains only the tandem KH1-KH2 domains is a stable well-folded unit suitable for detailed structural and functional characterization. Using this KH1-KH2 construct we explicitly test a hypothesis that has been proposed to explain the effect of the Ile fi Asn mutation that it causes complete unfolding of the protein. Here we show that the I307N point mutation does not completely unfold the KH domain. The KH1-KH2 construct bearing I307N substitution is stable in isolation and adopts a native-like .

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