Comprehensive mapping of mutations in the C9ORF72 that affect folding and binding to SMCR8 protein. (October 2022)

• Record Type: Journal Article
• Authors: Xue, Bin; Li, Ruiting; Ma, Haining; Rahaman, Abdul; Kumar, Vijay
• Is Part Of: Process biochemistry. Volume 121(2022)
• Page Start: 312
• Page End: 321
• Publication Date: 2022-10
• Subjects: C9orf72 -- SMCR8 -- Missense mutations -- Complex interface -- Stability -- Binding affinity; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2022.07.013
• Languages: English
• ISSNs: 1359-5113

Abstract

Abstract: Mutations of the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 protein interacts with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) and WDR41 to form a trimeric complex that regulates several cellular pathways including autophagy and membrane trafficking and is strongly linked to familial ALS and FTD. The C9orf72-SMCR8 complex is important for its GTPase activating proteins (GAP) activity and mutations in the dimer interface affects the GAP activity. Mutations at protein-protein interfaces alter the stability and binding affinity of protein-protein complexes and may lead to diseases. In this study, we used computational saturation mutagenesis, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations of C9orf72 protein stability and binding affinity to Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8). A total of 494 interfacial mutations of C9orf72 were analyzed, and we observed that most of these mutations destabilize the protein and decreased the binding to SMCR8. We further analyzed 240 annotated verified C9orf72 missense variations and revealed that most of the mutations affect the stability and the C9orf72-SMCR8 interaction. These findings shed light on the effect of mutations in C9orf72 stability and binding which can successfully predict the functional consequences of mutations on C9orf72 function and may enable researchers to deduce the mechanisms of ALS and FTD. Graphical Abstract: ga1 Highlights: C9orf72 (chromosome 9 open reading frame 72) mutations affect protein stability and binding. Most of the interfacial mutations destabilize the protein and decreased the binding of C9orf72 to SMCR8. The mutations in α11 residues (392−419) of C9orf72 may significantly change the binding affinity of the C9orf72-SMCR8 complex. Mutations at residue G403 destabilized C9orf72 and decreased its binding to SMCR8. Mutations H406Q, H406R, R407I, L410S, and T411R stabilized C9orf72 but at the same time decreased the binding of SMCR8.