Abstract：
:TDP-43 is a nuclear protein whose abnormal aggregates are implicated in ALS and FTLD. Recently, an Asn/Gln rich C-terminal segment of TDP-43 has been shown to produce aggregation in vitro and reproduce most of the protein's pathological hallmarks in cells, but little is known about this segment's structure. Here, CD and 2D heteronuclear NMR spectroscopies provide evidence that peptides corresponding to the wild type and mutated sequences of this segment adopt chiefly disordered conformations that, in the case of the wild type sequence, spontaneously forms a β-sheet rich oligomer. Moreover, MD simulation provides evidence for a structure consisting of two β-strands and a well-defined, yet non-canonical structural element. Furthermore, MD simulations of four pathological mutations (Q343R, N345K, G348V and N352S) occurring in this segment predict that all of them could affect this region's structure. In particular, the Q343R variant tends to stabilize disordered conformers, N345K permits the formation of longer, more stable β-strands, and G348V tends to shorten and destabilize them. Finally, N352S acts to alter the β-stand register and when S352 is phosphorylated, it induces partial unfolding. Our results provide a better understanding of TDP-43 aggregation process and will be useful to design effectors capable to modulate its progression.
journal_name
Arch Biochem Biophysjournal_title
Archives of biochemistry and biophysicsauthors
Mompeán M,Buratti E,Guarnaccia C,Brito RM,Chakrabartty A,Baralle FE,Laurents DVdoi
10.1016/j.abb.2014.01.007subject
Has Abstractpub_date
2014-03-01 00:00:00pages
53-62eissn
0003-9861issn
1096-0384pii
S0003-9861(14)00017-4journal_volume
545pub_type
杂志文章abstract：:Functional concerns regarding hemoglobin-based red cell substitutes have generally centered on two parameters: (a) oxygen binding and delivery properties and (b) stabilization of the hemoglobin tetramer to prevent dimerization. Strategic chemical cross-linking and site-directed mutagenesis have produced proteins that ...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1995.1061
更新日期：1995-01-10 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(85)90219-x
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(89)90391-3
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pub_type： 杂志文章
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
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更新日期：1990-09-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(92)90135-j
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1997.0562
更新日期：1998-03-15 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1993.1277
更新日期：1993-06-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(92)90499-m
更新日期：1992-05-15 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/j.abb.2007.09.009
更新日期：2007-12-01 00:00:00
abstract：:Antisera against peptides from the extreme N- and C-terminal regions of the VDR were evaluated. The N-terminal antiserum Ab192 functioned as a general-purpose antibody, being able to supershift the rhVDR in heterodimeric or homodimeric binding complexes in the EMSA, and detect both recombinant and native forms of the ...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1997.0481
更新日期：1998-01-15 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章,评审
doi：10.1016/j.abb.2009.07.011
更新日期：2010-01-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(87)90374-2
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1993.1275
更新日期：1993-06-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章,评审
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更新日期：2013-03-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/j.abb.2011.07.014
更新日期：2011-10-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.2000.2195
更新日期：2001-02-01 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.2001.2548
更新日期：2001-10-15 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.2000.2077
更新日期：2000-12-15 00:00:00
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journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.2000.1794
更新日期：2000-05-15 00:00:00
abstract：:Iron-sulfur [Fe-S] clusters are ubiquitous ancient prosthetic groups that are required to sustain fundamental life processes. Formation of intracellular [Fe-S] clusters does not occur spontaneously but requires a complex biosynthetic machinery. Different types of [Fe-S] cluster assembly systems have been discovered. A...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章,评审
doi：10.1016/j.abb.2007.12.014
更新日期：2008-06-15 00:00:00
abstract：:Rabbit and human brain tryptophan hydroxylase were cloned and expressed in Escherichia coli. Each of the respective cDNAs, including the complete coding sequence of tryptophan hydroxylase, was obtained by reverse transcription of rabbit or human brain mRNA and subcloned into the expression vector pET-3C. The expressed...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1006/abbi.1994.1523
更新日期：1994-12-01 00:00:00
abstract：:The spectral properties of 4-methylumbelliferyl-glycosides (MeUmb-glycosides) were investigated in order to assess their usefulness as probes of the microenvironment of sugar binding sites on lectin molecules. It was shown that the abnormally high values for fluorescence polarization of free MeUmb-glycosides (from 0.0...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(84)90584-8
更新日期：1984-08-01 00:00:00
abstract：:A basic, dimeric myotoxic protein, myotoxin II, purified from Bothrops asper venom has a similar molecular weight and is immunologically cross-reactive with antibodies raised to previously isolated B. asper phospholipases A2, except that it shows only 0.1% of the phospholipase activity against L-alpha-phosphatidylchol...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/0003-9861(91)90307-5
更新日期：1991-02-01 00:00:00
abstract：:Heavy-atom isotope effects for the N-demethylation of nicotine have been determined in vivo in static-phase biosynthetically incompetent plant cell cultures of Nicotiana species. A (2)H kinetic isotope effect of 0.587 and a (15)N kinetic isotope effect of 1.0028 were obtained. An identical (15)N kinetic isotope effect...
journal_title：Archives of biochemistry and biophysics
pub_type： 杂志文章
doi：10.1016/j.abb.2006.12.013
更新日期：2007-02-15 00:00:00
