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Download Jan 31 4285 Lecture 4
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Ubiquitin – Amino Acid Conservation * * Ubiquitin – Nucleotide Conservation * * * * * * * * * * * * * * * * * * Amino Acid Conservation in Critical Domains 11_03.jpg Errors in Protein Function • Eg. Cystic Fibrosis • Mutation causes loss-of-function • High occurrence of error may be a result of a heterozygote advantage Nature 393, 79 - 82 (07 May 1998) Salmonella typhi uses CFTR to enter intestinal epithelial cells GERALD B. PIER*, MARTHA GROUT*, TANWEER ZAIDI*, GLORIA MELULENI*, SIMONE S. MUESCHENBORN*, GEORGE BANTING†, ROSEMARY RATCLIFF‡, MARTIN J. EVANS§ & WILLIAM H. COLLEDGE‡ 11_07.jpg 11_09.jpg 11_10.jpg 11_10_2.jpg 11_10_3.jpg 11_16.jpg 11_16_2.jpg 11_11.jpg 11_11_2.jpg 11_12.jpg 11_13.jpg 11_05.jpg 11_05_2.jpg Huntington’s Disease • CAG repeat codes for glutamine (Q) • polyQ located near the N-terminus of Huntingtin protein • Expansion in the coding region of the gene (unlike, for eg. FMR1 – Fragile X syndrome - expansion is in 5’ UTR ) Huntington’s Disease MATLEKLMKA QPLLPQPQPP PEFQKLLGIA APRSLRAALW FGNFANDNEI LVPVEDEHST ELTLHHTQHQ SIVELIAGGG AASSGVSTPG FESLKSFQQQ QQQQQQQQQQ PPPPPPPPGP AVAEEPLHRP MELFLLCSDD AESDVRMVAD RFAELAHLVR PQKCRPYLVN KVLLKAFIAN LKSSSPTIRR LLILGVLLTL RYLVPLLQQQ DHNVVTGALE LLQQLFRTPP SSCSPVLSRK QKGKVLLGEE SAGHDIITE……… QQQQQQQQQQ KKELSATKKD ECLNKVIKAL LLPCLTRTSK TAAGSAVSIC VKDTSLKGSF PELLQTLTAV EALEDDSESR PPPPPPPPPP RVNHCLTICE MDSNLPRLQL RPEESVQETL QHSRRTQYFY GVTRKEMEVS GGIGQLTAAK SDVSSSALTA PQLPQPPPQA NIVAQSVRNS ELYKEIKKNG AAAVPKIMAS SWLLNVLLGL PSAEQLVQVY EESGGRSRSG SVKDEISGEL MATLEKLMKA QQQQQQQQQQ AVAEEPLHRP AESDVRMVAD PQKCRPYLVN LKSSSPTIRR RYLVPLLQQQ LLQQLFRTPP QKGKVLLGEE FESLKSFQQQ QQQQQQQQQQ KKELSATKKD ECLNKVIKAL LLPCLTRTSK TAAGSAVSIC VKDTSLKGSF PELLQTLTAV EALEDDSESR QQQQQQQQQQ PQLPQPPPQA NIVAQSVRNS ELYKEIKKNG AAAVPKIMAS SWLLNVLLGL PSAEQLVQVY EESGGRSRSG SVKDEISGEL QQQQQQQQQQ QPLLPQPQPP PEFQKLLGIA APRSLRAALW FGNFANDNEI LVPVEDEHST ELTLHHTQHQ SIVELIAGGG AASSGVSTPG QQQQQQQQQQ PPPPPPPPGP MELFLLCSDD RFAELAHLVR KVLLKAFIAN LLILGVLLTL DHNVVTGALE SSCSPVLSRK SAGHDIITE… QQQQQQQQQQ PPPPPPPPPP RVNHCLTICE MDSNLPRLQL RPEESVQETL QHSRRTQYFY GVTRKEMEVS GGIGQLTAAK SDVSSSALTA Huntington CAG Repeat P.Sudbery, Human Molecular Genetics 2nd ed, Prentice Hall. PCR analysis of CAG repeat length in family with Huntington’s disease Huntington’s Disease GFP-Huntingtin GFP-polyQ138-Huntingtin Xia et al., Human Molecular Genetics, 2003, Vol. 12, No. 12 1393-1403 Heterozygous knockouts are normal! Transgenic Mouse
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