Molecular interactions between C9ORF72 and SMCR8: A local energetic frustration perspective

Abstract

The hexanucleotide repeat expansion in C9orf72 represents a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9orf72, together with SMCR8 and WDR41, can form a stable complex that regulates autophagy and membrane trafficking. Very recently, the cryo-EM structure of C9orf72-SMCR8-WDR41 helps in understanding the structure-function relationship of C9orf72. This protein complex is indispensable to several cellular processes and is strongly linked to familial ALS and FTD. Understanding the molecular basis of the C9orf72-SMCR8 protein-protein interaction is thus important to comprehend their function. To establish a basis for understanding the relationships between sequence, structure, and function of the C9orf72, this study reports a local frustration analysis on the C9orf72-SMCR8 complex structure. An analysis of local frustration profiles indicated that (1) the structural domains in C9orf72 are minimally-frustrated and relatively conserved, (2) high frustration patches on the protein-protein interface (3) increased frustration in the C-terminal helices involved in the dimerization of C9orf72 structures.