7SP0

Crystal structure of human SFPQ L534I mutant in complex with zinc

7SP0 の概要

• エントリーDOI: 10.2210/pdb7sp0/pdb
• 分子名称: Splicing factor, proline- and glutamine-rich, ZINC ION (3 entities in total)
• 機能のキーワード: sfpq, dbhs protein, rrm, zn, polymerization, nuclear protein, als mutation, rna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60318.91

構造登録者

Lee, M. (登録日: 2021-11-01, 公開日: 2022-10-12, 最終更新日: 2023-10-18)

主引用文献

Widagdo, J.,Udagedara, S.,Bhembre, N.,Tan, J.Z.A.,Neureiter, L.,Huang, J.,Anggono, V.,Lee, M.
Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons.
Open Biology, 12:220187-220187, 2022

PubMed Abstract: Splicing factor proline- and glutamine-rich (SFPQ) is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating centre (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a second zinc-binding site revealed by the 1.83 Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

PubMed: 36168806
DOI: 10.1098/rsob.220187

実験手法

X-RAY DIFFRACTION (1.83 Å)