Biophysical controls: motors looping DNA (Introduction)

by David Turell , Friday, November 10, 2023, 15:54 (169 days ago) @ David Turell

Major complexities:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/10_november_2023/41...

"Many protein complexes that drive key processes in cells are “molecular motors”—assemblies that consume (electro)chemical energy to produce mechanical work. Examples include the FoF1 synthase rotary motor that catalyzes adenosine triphosphate (ATP) production, kinesin and myosin motors that “walk” along cytoskeleton filaments, or polymerases and helicases that move along DNA. Structural-maintenance of chromosomes protein complexes (SMCs) have only recently been identified as an entirely distinct class of DNA-translocating motors, although their key role in folding the linear DNA double helix into intricate three-dimensional structures, such as X-shaped mitotic chromosomes, was known for decades. Here, we discuss how insights from biophysical, biochemical, and structural studies are starting to yield an understanding of the mechanism by which these motors extrude loops of DNA to structure genomes.

"SMCs are evolutionarily conserved from bacteria to humans. Eukaryotes feature three main classes of SMCs: condensin, which assembles mitotic chromosomes during cell division; cohesin, which regulates interphase chromosome structure and links sister chromatids (the two copies of every chromosome generated by DNA replication); and SMC5/6, which has less well understood roles in DNA damage repair and replication. All of these complexes exhibit a similar tripartite ring architecture of ∼40 nm in diameter made of a dimer of coiledcoil SMC proteins and an intrinsically disordered kleisin protein, to which additional subunits attach. In the case of cohesin and condensin, these additional subunits are built from multiple repeats of “HEAT” motifs, referred to here as HEAT-A and HEAT-B subunits. At the heart of the motor are two globular ATPase head domains located at the ends of the SMC coiled coils.

"SMCs generate DNA loops, which appear to be the basic motif of chromosome structure that underlie many major genomic processes, from folding mitotic chromosomes to the formation of topologically associating domains [TADs (genomic domains thought to regulate gene expression)]. Whereas earlier chromosome conformation capture mapping and polymer simulations suggested that extrusion of DNA loops by SMCs could explain many chromosomal features, direct evidence for such loop extrusion by SMCs was provided by single-molecule studies that visualized the formation of DNA loops in real time.

"These studies yielded a wealth of data. Driven by ATP hydrolysis, SMCs were found to be very fast motors, reeling in DNA at a speed of ∼1 kilobase pair per second in a directional and processive manner for long distances. ATP binding induces SMCs to take a step of hundreds of base pairs—strikingly different from previously characterized DNA-translocating motors that typically move a single base pair at a time. Such large steps are consistent with studies that implicated conformational changes of SMC structure that were the approximate size of the entire complex in the DNA loop extrusion process. Although fast, SMCs are also weak motors that stall if subpiconewton forces are applied to the DNA that they reel in. Another unexpected feature of SMCs is their ability to pass DNA binding proteins, such as nucleosomes, polymerases, or even other SMCs, and incorporate them into the extruded DNA loops." (my bold)

Comment: the article goes on to theorize about exact underlying forces and methods to be further studied. Note my bold: 1,000 base per second speed!!! Not by chance!!