Protein-protein Interactions As a Strategy Towards Protein-specific Drug Design: the Example of Ataxin-1

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Oct 25

PMID 24155902

Citations 8

Authors

Cesira de Chiara

Rajesh P Menon

Geoff Kelly

Annalisa Pastore

Affiliations

Soon will be listed here.

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.

Citing Articles

Toward the design and development of peptidomimetic inhibitors of the Ataxin-1 aggregation pathway.

Miceli M, Deriu M, Grasso G Biophys J. 2022; 121(23):4679-4688.

PMID: 36262042 PMC: 9748251. DOI: 10.1016/j.bpj.2022.10.021.

A Structural Study of the Cytoplasmic Chaperone Effect of 14-3-3 Proteins on Ataxin-1.

Leysen S, Burnley R, Rodriguez E, Milroy L, Soini L, Adamski C J Mol Biol. 2021; 433(19):167174.

PMID: 34302818 PMC: 8505757. DOI: 10.1016/j.jmb.2021.167174.

ATXN1 N-terminal region explains the binding differences of wild-type and expanded forms.

Rocha S, Vieira J, Vazquez N, Lopez-Fernandez H, Fdez-Riverola F, Reboiro-Jato M BMC Med Genomics. 2019; 12(1):145.

PMID: 31655597 PMC: 6814966. DOI: 10.1186/s12920-019-0594-4.

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch.

Kuiper E, de Mattos E, Jardim L, Kampinga H, Bergink S Front Neurosci. 2017; 11:145.

PMID: 28386214 PMC: 5362620. DOI: 10.3389/fnins.2017.00145.

Energy landscapes of functional proteins are inherently risky.

Gershenson A, Gierasch L, Pastore A, Radford S Nat Chem Biol. 2014; 10(11):884-91.

PMID: 25325699 PMC: 4416114. DOI: 10.1038/nchembio.1670.

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