A ubiquitin-like domain is required for stabilizing the N-terminal ATPase module of human SMCHD1

Lars C Pedersen,Natalie D Shaw,Lalith Perera,Kaoru Inoue,Susan Kim

doi:10.1038/s42003-019-0499-y

Abstract

Variants in the gene SMCHD1, which encodes an epigenetic repressor, have been linked to both congenital arhinia and a late-onset form of muscular dystrophy called facioscapulohumeral muscular dystrophy type 2 (FSHD2). This suggests that SMCHD1 has a diversity of functions in both developmental time and space. The C-terminal end of SMCHD1 contains an SMC-hinge domain which mediates homodimerization and chromatin association, whereas the molecular architecture of the N-terminal region, which harbors the GHKL-ATPase domain, is not well understood. We present the crystal structure of the human SMCHD1 N-terminal ATPase module bound to ATP as a functional dimer. The dimer is stabilized by a novel N-terminal ubiquitin-like fold and by a downstream transducer domain. While disease variants map to what appear to be critical interdomain/intermolecular interfaces, only the FSHD2-specific mutant constructs we tested consistently abolish ATPase activity and/or dimerization. These data suggest that the full functional profile of SMCHD1 has yet to be determined.

Highlights

Variants in the gene SMCHD1, which encodes an epigenetic repressor, have been linked to both congenital arhinia and a late-onset form of muscular dystrophy called facioscapulohumeral muscular dystrophy type 2 (FSHD2)
SMCHD1 has traditionally been classified as an atypical member of the SMC family of proteins, the overall structure reveals greater similarity to the MORC family of gene repressors[19,20]
In family members of the GHL subset of GHKL-ATPases, ATP binding induces major conformational changes that optimally position the catalytic residues for ATP hydrolysis, stabilize the dimeric state, and generate a client-binding cavity

Summary

Introduction

Variants in the gene SMCHD1, which encodes an epigenetic repressor, have been linked to both congenital arhinia and a late-onset form of muscular dystrophy called facioscapulohumeral muscular dystrophy type 2 (FSHD2). While disease variants map to what appear to be critical interdomain/intermolecular interfaces, only the FSHD2-specific mutant constructs we tested consistently abolish ATPase activity and/or dimerization These data suggest that the full functional profile of SMCHD1 has yet to be determined. The GHKL (gyrase, Hsp[90], histidine kinase, and MutL) superfamily of ATPases/kinases includes a group of functionally unrelated proteins unified by the presence of an unconventional ATP-binding fold (the Bergerat fold) at their Nterminal[1,2,3]. This fold includes a GHKL-ATPase core domain and an adjacent α/ß domain referred to as the transducer domain and formerly, the S5 domain[1]. Terminal ends thereby forms a molecular clamp around a DNA or peptide client whereby release of the clamp is coupled to ATP hydrolysis[1]

Methods

Results

Conclusion