Work

Disorder Mediated Oligomerization of DISC1 Proteins Revealed by Coarse-Grained Molecular Dynamics Simulations

Year: 2019

Type: article

Abstract: Disrupted-in-Schizophrenia-1 (DISC1) is a scaffold protein of significant importance for neurodevelopment and a prominent candidate protein in the etiology of mental disorders. In this work, we investigate the role of conformational heterogeneity and local structural disorder in the oligomerization pathway of the full-length DISC1 and of two truncation variants. Through extensive coarse-grained molecular dynamics simulations with a predictive energy landscape based model, we reveal the general mechanistic principles of DISC1 oligomerization. We found that both conformational heterogeneity and structural disorder play an important role in the dimerization pathway of DISC1. This study sheds light on the differences in oligomerization pathways of the full-length protein compared to the truncated variants produced by a chromosomal translocation associated with schizophrenia.

Source: The Journal of Physical Chemistry B

DOI: 10.1021/acs.jpcb.9b07467

Authors: Julien Roche, Davit A. Potoyan

Institution: Iowa State University

Language: English

Topic: Protein Structure and Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Roy J. Carver Charitable Trust, Iowa State University, National Institute of General Medical Sciences

Award: G7153603124