2M41

Solution Structure of the AXH domain of Ataxin-1 in complex with ligand peptide from Capicua

2M41 の概要

• エントリーDOI: 10.2210/pdb2m41/pdb
• 関連するPDBエントリー: 1OA8 1V06
• NMR情報: BMRB: 18982
• 分子名称: Protein capicua homolog, Ataxin-1 (2 entities in total)
• 機能のキーワード: protein/protein, ataxin-1 axh-cic complex, transcription regulator
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus (Potential): Q96RK0; Cytoplasm (By similarity): P54253
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 15502.67

構造登録者

de Chiara, C.,Kelly, G.,Pastore, A. (登録日: 2013-01-28, 公開日: 2013-12-11, 最終更新日: 2024-05-15)

主引用文献

de Chiara, C.,Menon, R.P.,Kelly, G.,Pastore, A.
Protein-Protein Interactions as a Strategy towards Protein-Specific Drug Design: The Example of Ataxin-1.
Plos One, 8:e76456-e76456, 2013

PubMed Abstract: A main challenge for structural biologists is to understand the mechanisms that discriminate between molecular interactions and determine function. Here, we show how partner recognition of the AXH domain of the transcriptional co-regulator ataxin-1 is fine-tuned by a subtle balance between self- and hetero-associations. Ataxin-1 is the protein responsible for the hereditary spinocerebellar ataxia type 1, a disease linked to protein aggregation and transcriptional dysregulation. Expansion of a polyglutamine tract is essential for ataxin-1 aggregation, but the sequence-wise distant AXH domain plays an important aggravating role in the process. The AXH domain is also a key element for non-aberrant function as it intervenes in interactions with multiple protein partners. Previous data have shown that AXH is dimeric in solution and forms a dimer of dimers when crystallized. By solving the structure of a complex of AXH with a peptide from the interacting transcriptional repressor CIC, we show that the dimer interface of AXH is displaced by the new interaction and that, when blocked by the CIC peptide AXH aggregation and misfolding are impaired. This is a unique example in which palindromic self- and hetero-interactions within a sequence with chameleon properties discriminate the partner. We propose a drug design strategy for the treatment of SCA1 that is based on the information gained from the AXH/CIC complex.

PubMed: 24155902
DOI: 10.1371/journal.pone.0076456

実験手法

SOLUTION NMR