L9: Extra reading Flashcards
SMC complex structure?
Hoencamp & Rowland (2023)
SMC complexes are conserved throughout the tree of life. The foundation of these complexes is a dimer of SMC proteins. Each SMC protein has a ~50-nm long coiled coil arm, with a dimerization interface on either end. The head domains of both SMC proteins of the dimer interact to form a composite ABC-like ATPase that can bind and hydrolyse two molecules of ATP. The head domains are bridged by a third protein, the kleisin subunit, to essentially form a ring-shaped complex (Fig. 1b). The ring-shaped core complex is complemented by accessory subunits, which, in case of cohesin and condensin, includes HEAT repeat proteins associated with kleisin (HAWK) proteins11.
SMC loop formation?
Hoencamp & Rowland (2023)
Through what is currently referred to as loop extrusion, these complexes can build loops by reeling in large segments of DNA23, which at least in the case of cohesin and condensin can include histones and other potential extrusion obstacles24.
Loop extrusion likely involves a cycle of concerted conformational changes that are driven by the ATPase machinery of the SMC subunits.
cohesin function?
The first SMC complex known to act when cells enter G1 phase is cohesin28,29. The action of cohesin on DNA is dynamic and involves cycles of loading, the formation of small loops, their enlargement and ultimately DNA release and concomitant loop loss. Cohesin loading depends on NIPBLSCC2, which together with MAU2SCC4 forms the cohesin loader complex30. NIPBLSCC2, however, is also essential for the loop extrusion process itself31,32. DNA release involves the cohesin release factor WAPL, which causes the opening of a DNA exit gate in cohesin rings33,34,35,36,37,38,39. The resulting loop loss enables cohesin to form new loops, which keeps the 3D configuration of the genome dynamic40,41,42 (Fig. 2a). When cohesin forms chromatin loops, it does so in a bi-directional manner31,32,45. This means that cohesin enlarges a loop towards both sides of the DNA. Cohesin enlarges loops until it encounters CTCF, which can act as a barrier for cohesin46,47. This presumably is why cohesin is found enriched at CTCF sites48,49,50.
mitotic kinases importance
Mitotic kinesins are found abnormally expressed in many cancer types, making them primary targets to stall uncontrolled cell division for anticancer therapy56. Inhibition of Eg5 by targeting a flexible loop of its motor domain (loop 5) causes mitotic arrest57,58 and inhibition of CENP-E and KIF18A stops cell proliferation and tumorigenesis59. The inhibition of KIFC1 (also known as HSET) selectively targets cancer cells60, because this motor is upregulated to prevent mitotic defects in cancer cells with multiple centrosomes61,62. However, mitotic inhibitors, including those that target kinesins63, often fail in the clinic owing to drug resistance, off-target effects and redundancies between kinesins (for example, Eg5 and KIF15)44,64. Future work is required to reduce the off-target effects and analyse the efficacy of kinesin inhibitors in combination with other anticancer therapeutics.
Yildiz (2025)
this is sort of for L11 too
The motor domain of kinesin is approximately tenfold smaller than that of dynein75 and consists of eight β-sheets sandwiched between three α-helices on each side76 (Fig. 1c). The nucleotide-binding cleft (NBC) of kinesin is highly conserved and structurally related to G proteins77. Loop 7 (P-loop) binds to the α- and β-phosphates of ATP and coordinates the Mg2+ ion for tight binding of the nucleotide76 (Fig. 1c). The P-loop communicates with loop 9 (Switch I) and loop 11 (Switch II), which undergo nucleotide-dependent conformational changes and communicate the status of the bound nucleotide to the microtubule-binding interface (helix 4 and loops 7, 8 and 12)78,79.
Adjacent to the motor domain, kinesins contain a short unstructured neck region that docks and undocks from the motor domain in a nucleotide-dependent manner5 (Fig. 1c). N-kinesins contain a 14- to 18-amino-acid-long neck linker that connects the motor domain to the stalk and provides the separation needed for motor domains to bind to adjacent tubulin sites9
Yildiz (2025)
centrosome structure?
Hoffman (2021)
During each round of cell division, cells replicate their genome once and assemble mitotic spindles to ensure accurate segregation of the duplicated chromosomes. In addition to replicating their DNA, cells also duplicate their centrosome, a non-membrane bound organelle. Centrosomes serve as major microtubule-organizing centers (MTOCs) in animal cells and therefore play key roles in regulating spindle formation, chromosome segregation and cytokinesis but also polarity and motility. A new cell cycle typically begins with a single centrosome, that contains a pair of centrioles, an older parent centriole and a tightly associated younger procentriole. Centrioles are evolutionarily conserved barrels composed of microtubule triplets arranged in a nine-fold symmetry [1] and are surrounded by a protein matrix, the pericentriolar material (PCM) to form the centrosome. The PCM is responsible for microtubule (MT) nucleation which requires the recruitment of γ-tubulin ring complexes (γ-TuRCs) from the cytoplasm.
