4O66

Crystal Structure of SMARCAL1 HARP substrate recognition domain

Summary for 4O66

• Entry DOI: 10.2210/pdb4o66/pdb
• Descriptor: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1, SULFATE ION, SODIUM ION, ... (4 entities in total)
• Functional Keywords: dna repair dna replication, dna binding protein
• Biological source: Mus musculus (mouse)
• Cellular location: Nucleus (By similarity): Q8BJL0
• Total number of polymer chains: 4
• Total formula weight: 34902.91

Authors

Mason, A.C.,Eichman, B.F. (deposition date: 2013-12-20, release date: 2014-05-14, Last modification date: 2024-02-28)

Primary citation

Mason, A.C.,Rambo, R.P.,Greer, B.,Pritchett, M.,Tainer, J.A.,Cortez, D.,Eichman, B.F.
A structure-specific nucleic acid-binding domain conserved among DNA repair proteins.
Proc.Natl.Acad.Sci.USA, 111:7618-7623, 2014

PubMed Abstract: SMARCAL1, a DNA remodeling protein fundamental to genome integrity during replication, is the only gene associated with the developmental disorder Schimke immuno-osseous dysplasia (SIOD). SMARCAL1-deficient cells show collapsed replication forks, S-phase cell cycle arrest, increased chromosomal breaks, hypersensitivity to genotoxic agents, and chromosomal instability. The SMARCAL1 catalytic domain (SMARCAL1(CD)) is composed of an SNF2-type double-stranded DNA motor ATPase fused to a HARP domain of unknown function. The mechanisms by which SMARCAL1 and other DNA translocases repair replication forks are poorly understood, in part because of a lack of structural information on the domains outside of the common ATPase motor. In the present work, we determined the crystal structure of the SMARCAL1 HARP domain and examined its conformation and assembly in solution by small angle X-ray scattering. We report that this domain is conserved with the DNA mismatch and damage recognition domains of MutS/MSH and NER helicase XPB, respectively, as well as with the putative DNA specificity motif of the T4 phage fork regression protein UvsW. Loss of UvsW fork regression activity by deletion of this domain was rescued by its replacement with HARP, establishing the importance of this domain in UvsW and demonstrating a functional complementarity between these structurally homologous domains. Mutation of predicted DNA-binding residues in HARP dramatically reduced fork binding and regression activities of SMARCAL1(CD). Thus, this work has uncovered a conserved substrate recognition domain in DNA repair enzymes that couples ATP-hydrolysis to remodeling of a variety of DNA structures, and provides insight into this domain's role in replication fork stability and genome integrity.

PubMed: 24821763
DOI: 10.1073/pnas.1324143111

Experimental method

X-RAY DIFFRACTION (1.9 Å)