MtSnf2
From Proteopedia
Myceliophthora thermophila Sucrose Non-Fermenting 2
The crystal structure of Snf2 (MtSnf2, residues 445-1176) from the yeast Myceliophthora thermophila was determined, revealing key characteristics of the protein's inactive, ground state conformation. [1]
FunctionSnf2 proteins are a family of ATP-dependent chromatin remodelers that regulate access to genomic DNA. Although they are classified as helicase-like proteins within Superfamily 2, they do not separate nucleic acid strands; they function as DNA translocases that utilize energy from ATP hydrolysis to apply torsional strain to DNA. This mechanical force allows them to alter the structure or position of nucleosomes, which is essential for overcoming the barrier chromatin poses to genetic processes such as transcription, replication, and DNA repair. The specific functions of Snf2 proteins are diverse and regulated by their associated complexes, leading to various remodeling outcomes. These activities include sliding nucleosomes to change their spacing or translational position, assembling and disassembling nucleosomes, and exchanging canonical histones for variants like H2A.Z or H3.3. Through these mechanisms, Snf2 proteins play critical roles in maintaining genome stability, such as defining centromeric and telomeric chromatin, and are increasingly recognized for their involvement in the DNA-damage response (DDR), where they facilitate access for repair machinery with homologous recombination.[2] DiseaseMutations in the sequence has association with rare Neurodevelopmental Disorders (SSRIDDs) Germline heterozygous loss-of-function or dominant-negative variants in SWI/SNF genes cause SWI/SNF-related intellectual disability disorders (SSRIDDs), including Coffin-Siris syndrome (CSS; e.g., SMARCA4, ARID1B) and Nicolaides-Baraitser syndrome (NCBRS; SMARCA2 missense in ATPase domain), featuring intellectual disability, speech delay, seizures, coarse facies, and digital hypoplasia. Mutations disrupt neuron-specific BAF assembly during cortical development and synaptic plasticity, converging on severe neurodevelopmental phenotypes with high mutational burden in structural hubs. PRC2-SWI/SNF antagonism is perturbed, as BAF loss derepresses polycomb targets, exacerbating developmental gene dysregulation.[3] Mutations in genes that encode proteins of the SWI/SNF complex, called BAF complex in mammals, cause a spectrum of disorders that ranges from syndromic intellectual disability to Coffin-Siris syndrome (CSS) to Nicolaides-Baraitser syndrome (NCBRS).
Structural highlightsThe DNA binding sites of MtSnf2 remain fully exposed even in its inactive state suggesting that the protein maintains a poised state for helicase activity with the ATP-ase site regulated. The catalytic core of MtSnf2 is structurally divided into two major portions: Lobe 1 and Lobe 2. Lobe 1 consists of the post-HSA (helicase/SANT-associated) domain and the first RecA-like core domain (Core 1). Lobe 2 contains the second RecA-like core domain (Core 2) and the C-terminal SnAc domain. The structure is held in an inactive state by the direct stacking and interaction between the two RecA-like core domains. This interaction twists the essential ATP-binding motifs, Motif I (P loop) and Motif VI (arginine fingers), toward opposite directions, effectively blocking their direct contact and explaining the protein's inactivity in the ground state. The primary interaction occurs at the interface where Core 1, via the &alpha 5 helix, makes hydrophobic contact with from the &beta 7 of the Core 2 domain, burying a solvent-inaccessible surface area. Perturbing this interaction, such as with the T616D V797D double mutation, significantly increases the basal ATPase activity by a factor of 5. Additionally, the post-HSA domain binds to Core 1, specifically interacting with the last helix, which is redefined as the suppressor helix(). Finally, the C-terminal SnAc domain meanders at the surface of Core 2, covering a large area (over 2,300 angstrom.sq.), and plays a key role in stabilizing the Core 2 domain while making little contact with Core 1. [4]
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