Disorder mediated oligomerization of DISC1 proteins revealed by coarse-grained computer simulations.

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.