6NLH

Structure of human triose phosphate isomerase R189A

Summary for 6NLH

• Entry DOI: 10.2210/pdb6nlh/pdb
• Descriptor: Triosephosphate isomerase, SODIUM ION, BROMIDE ION, ... (5 entities in total)
• Functional Keywords: isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 210990.36

Authors

Richards, K.R.,Roland, B.P.,Palladino, M.J.,VanDemark, A.P. (deposition date: 2019-01-08, release date: 2019-06-19, Last modification date: 2023-10-11)

Primary citation

Roland, B.P.,Richards, K.R.,Hrizo, S.L.,Eicher, S.,Barile, Z.J.,Chang, T.C.,Savon, G.,Bianchi, P.,Fermo, E.,Ricerca, B.M.,Tortorolo, L.,Vockley, J.,VanDemark, A.P.,Palladino, M.J.
Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo.
Biochim Biophys Acta Mol Basis Dis, 1865:2257-2266, 2019

PubMed Abstract: Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI/TPI patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

PubMed: 31075491
DOI: 10.1016/j.bbadis.2019.05.002

Experimental method

X-RAY DIFFRACTION (2.199 Å)