4Y0F

Crystal Structure of Human TDP-43 RRM1 Domain in Complex with an Unmodified Single-stranded DNA

Summary for 4Y0F

• Entry DOI: 10.2210/pdb4y0f/pdb
• Related: 4Y00
• Descriptor: TAR DNA-binding protein 43, DNA (5'-D(*GP*TP*TP*GP*AP*GP*CP*GP*TP*T)-3') (3 entities in total)
• Functional Keywords: rna recognition motif 1 complex, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q13148
• Total number of polymer chains: 4
• Total formula weight: 30311.54

Authors

Chiang, C.H.,Kuo, P.H.,Doudeva, L.G.,Wang, Y.T.,Yuan, H.S. (deposition date: 2015-02-06, release date: 2016-02-10, Last modification date: 2023-11-08)

Primary citation

Chiang, C.H.,Grauffel, C.,Wu, L.S.,Kuo, P.H.,Doudeva, L.G.,Lim, C.,Shen, C.K.,Yuan, H.S.
Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation
Sci Rep, 6:21581-21581, 2016

PubMed Abstract: The RNA-binding protein TDP-43 forms intracellular inclusions in amyotrophic lateral sclerosis (ALS). While TDP-43 mutations have been identified in ALS patients, how these mutations are linked to ALS remains unclear. Here we examined the biophysical properties of six ALS-linked TDP-43 mutants and found that one of the mutants, D169G, had higher thermal stability than wild-type TDP-43 and that it was cleaved by caspase 3 more efficiently, producing increased levels of the C-terminal 35 kD fragments (TDP-35) in vitro and in neuroblastoma cells. The crystal structure of the TDP-43 RRM1 domain containing the D169G mutation in complex with DNA along with molecular dynamics simulations reveal that the D169G mutation induces a local conformational change in a β turn and increases the hydrophobic interactions in the RRM1 core, thus enhancing the thermal stability of the RRM1 domain. Our results provide the first crystal structure of TDP-43 containing a disease-linked D169G mutation and a disease-related mechanism showing that D169G mutant is more susceptible to proteolytic cleavage by caspase 3 into the pathogenic C-terminal 35-kD fragments due to its increased stability in the RRM1 domain. Modulation of TDP-43 stability and caspase cleavage efficiency could present an avenue for prevention and treatment of TDP-43-linked neurodegeneration.

PubMed: 26883171
DOI: 10.1038/srep21581

Experimental method

X-RAY DIFFRACTION (2.648 Å)