SMCHD1's ubiquitin-like domain is required for N-terminal dimerization and chromatin localization
- Author(s)
- Gurzau, AD; Horne, C; Mok, YF; Iminitoff, M; Willson, TA; Young, SN; Blewitt, ME; Murphy, JM;
- Journal Title
- Biochemical Journal
- Publication Type
- epub ahead of print
- Abstract
- Structural Maintenance of Chromosomes flexible Hinge Domain-containing 1 (SMCHD1) is an epigenetic regulator that mediates gene expression silencing at targeted sites across the genome. Our current understanding of SMCHD1's molecular mechanism, and how substitutions within SMCHD1 lead to the diseases, facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS), are only emerging. Recent structural studies of its two component domains - the N-terminal ATPase and C-terminal SMC hinge - suggest that dimerization of each domain plays a central role in SMCHD1 function. Here, using biophysical techniques, we demonstrate that the SMCHD1 ATPase undergoes dimerization in a process that is dependent on both the N-terminal UBL (Ubiquitin-like) domain and ATP binding. We show that neither the dimerization event, nor the presence of a C-terminal extension past the transducer domain, affect SMCHD1's in vitro catalytic activity as the rate of ATP turnover remains comparable to the monomeric protein. We further examined the functional importance of the N-terminal UBL domain in cells, revealing that its targeted deletion disrupts the localization of full-length SMCHD1 to chromatin. These findings implicate UBL-mediated SMCHD1 dimerization as a crucial step for chromatin interaction, and thereby for promoting SMCHD1-mediated gene silencing.
- Publisher
- Portland Press
- Keywords
- GHKL ATPase; SMC proteins; UBL domain; nucleic acid binding proteins; protein-protein interactions
- Research Division(s)
- Epigenetics And Development; Inflammation
- PubMed ID
- 34109974
- Publisher's Version
- https://doi.org/10.1042/bcj20210278
- Open Access at Publisher's Site
https://doi.org/10.1042/BCJ20210278- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-06-21 10:25:58
Last Modified: 2021-06-21 10:42:59