Hexameric NuMA:LGN structures promote multivalent interactions required for planar epithelial divisions

Abstract

Cortical force generators connect epithelial polarity sites with astral microtubules, allowing dynein movement to orient the mitotic spindle as astral microtubules depolymerize. Complexes of the LGN and NuMA proteins, fundamental components of force generators, are recruited to the cortex by Gαi-subunits of heterotrimeric G-proteins. They associate with dynein/dynactin and activate the motor activity pulling on astral microtubules. The architecture of cortical force generators is unknown. Here we report the crystal structure of NuMA:LGN hetero-hexamers, and unveil their role in promoting the assembly of active cortical dynein/dynactin motors that are required in orchestrating oriented divisions in polarized cells. Our work elucidates the basis for the structural organization of essential spindle orientation motors.

Oriented cell divisions in epithelia: from force generation to force anisotropy by tension, shape and vertices

“…In these studies, optogenetic recruitment of NuMA to the cortex was sufficient to orient the mitotic spindle [17,22]. By contrast and in agreement with other studies [19,20], recruitment of the dynein heavy chain/dynactin to the cortex was insufficient to generate pulling forces on the spindle [17,22]. This suggests that NuMA is not only required for dynein recruitment, but also for force production.…”

“…The current paradigm for force generation involves the recruitment of dynein and its cofactor dynactin to the cell cortex [7,8,[15][16][17][18]. However, recent studies indicate that cortical dynein recruitment is insufficient for OCD [19,20]. Here we discuss recent findings on dynein activity and how its interactors assist dynein in force generation [17,[19][20][21][22].…”

“…However, recent studies indicate that cortical dynein recruitment is insufficient for OCD [19,20]. Here we discuss recent findings on dynein activity and how its interactors assist dynein in force generation [17,[19][20][21][22].…”

“…Furthermore, NuMA localizes to MT tips in interphase and prometaphase cells, and deletion of the domain responsible for this localization (AA:1811-1985 in human) impaired spindle orientation in cultured keratinocytes and in vivo [20]. In addition, a second NuMA MT binding domain, (AA: 2002-2115 in human) is also essential for spindle orientation in cultured cells [19,21]. Accordingly, this second MT binding is necessary to orient the spindle upon optogenetic recruitment of NuMA to the cortex [17].…”

The crosstalk between microtubules, actin and membranes shapes cell division

“…Instead, coated plaques seem to be strictly related-in terms of molecular composition and independence from actin-to αvβ5 integrin-enriched structures that have been involved in adhesion during mitosis [92]. Importantly, in mitosis, canonical adhesion complexes are disassembled while adhesive structures resembling plaques are maintained to preserve the interaction with the [60] MTBD-2: Du et al [59] LipidBD-1: Kotak et al [63] LipidBD-2: Zheng et al [64] dyneinBD: Kotak et al [50] LGNBD: Pirovano et al [62] 4.1BD: Kiyomitsu & Cheeseman [66] GoLoco: Du & Macara [51] TPR: Du & Macara [51] DLG-BD: Saadaoui et al [ royalsocietypublishing.org/journal/rsob Open Biol. 10: 190314 substrate needed to achieve effective mitosis, daughter cell respreading and mitotic spindle orientation [19,[96][97][98][99] (see also §4.2 and 4.3).…”