3ktr

Structural highlights

Disease

[ATX2_HUMAN] Amyotrophic lateral sclerosis;Spinocerebellar ataxia type 2. Defects in ATXN2 are the cause of spinocerebellar ataxia type 2 (SCA2) [MIM:183090]; also known as olivopontocerebellar atrophy II (OPCA II or OPCA2). Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA2 is characterized by hyporeflexia, myoclonus and action tremor and dopamine-responsive parkinsonism. Note=SCA2 is caused by expansion of a CAG repeat resulting in about 36 to 52 repeats in some patients. Longer expansions result in earlier the expansion, onset of the disease.^{[1] [2] [3]} Defects in ATXN2 are a cause of susceptibility to amyotrophic lateral sclerosis type 13 (ALS13) [MIM:183090]. It is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Note=An increased risk for developing amyotrophic lateral sclerosis is seems to be conferred by CAG repeat intermediate expansions greater than 23 but below the threshold for developing spinocerebellar ataxia.^[4]

Function

[PABP1_HUMAN] Binds the poly(A) tail of mRNA. May be involved in cytoplasmic regulatory processes of mRNA metabolism such as pre-mRNA splicing. Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2. Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed.^{[5] [6]} [ATX2_HUMAN] Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.^[7]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996 Nov;14(3):269-76. PMID:8896555 doi:10.1038/ng1196-269
2. ↑ Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takahashi H, Tsuji S. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996 Nov;14(3):277-84. PMID:8896556 doi:10.1038/ng1196-277
3. ↑ Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Durr A, Didierjean O, Stevanin G, Agid Y, Brice A. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996 Nov;14(3):285-91. PMID:8896557 doi:10.1038/ng1196-285
4. ↑ Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rub U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. doi: 10.1038/nature09320. PMID:20740007 doi:10.1038/nature09320
5. ↑ Grosset C, Chen CY, Xu N, Sonenberg N, Jacquemin-Sablon H, Shyu AB. A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c-fos RNA coding determinant via a protein complex. Cell. 2000 Sep 29;103(1):29-40. PMID:11051545
6. ↑ Singh G, Rebbapragada I, Lykke-Andersen J. A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol. 2008 Apr 29;6(4):e111. doi: 10.1371/journal.pbio.0060111. PMID:18447585 doi:10.1371/journal.pbio.0060111
7. ↑ Nonis D, Schmidt MH, van de Loo S, Eich F, Dikic I, Nowock J, Auburger G. Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking. Cell Signal. 2008 Oct;20(10):1725-39. doi: 10.1016/j.cellsig.2008.05.018. Epub, 2008 Jun 15. PMID:18602463 doi:10.1016/j.cellsig.2008.05.018
8. ↑ Kozlov G, Safaee N, Rosenauer A, Gehring K. Structural basis of binding of P-body-associated proteins GW182 and ataxin-2 by the Mlle domain of poly(A)-binding protein. J Biol Chem. 2010 Apr 30;285(18):13599-606. Epub 2010 Feb 24. PMID:20181956 doi:10.1074/jbc.M109.089540