Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

Abstract

Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation. The Ran GTPase plays a key role in mitotic spindle assembly. However, how the generation of a chemical gradient of Ran-GTP at the spindle is coupled to mitotic post-translational modifications has never been characterized. Here, we solved the complex structure of Ran with the nucleotide release factor Mog1 and delineated a novel mitosis-specific acetylation-regulated Ran–Mog1 interaction during chromosome segregation. Our structure-guided functional analyses revealed that Mog1 competes with RCC1 for Ran binding in a GTP/GDP-dependent manner. Biochemical characterization demonstrated that Mog1-bound Ran prevents RCC1 binding and subsequent GTP loading. Surprisingly, Ran is a bona fide substrate of TIP60, and the acetylation of Lys134 by TIP60 liberates Mog1 from Ran binding during mitosis. Importantly, this acetylation-elicited switch of Ran binding to RCC1 promotes high level of Ran-GTP, which is essential for chromosome alignment. These results establish a previously uncharacterized regulatory mechanism in which TIP60 provides a homeostatic control of Ran-GTP level by tuning Ran effector binding for chromosome segregation in mitosis.

Mechanistic insights into the interaction of the MOG1 protein with the cardiac sodium channel Nav1.5 clarify the molecular basis of Brugada syndrome

“…5, A-C). To identify the underlying cause, we analyzed the affected amino acid residues against the 3D structure of MOG1 as reported by Bao et al (15). As shown in Fig.…”

“…MOG1 has an interesting structure with a backbone formed by six-stranded antiparallel ␤-sheets flanked on both sides by helices (14). The solution structure of human MOG1 was determined recently by conventional NMR spectroscopy and has a sandwich-like structure with nine ␤-strands and four helices (15). The ␤3 to ␤9 form the central antiparallel ␤-sheets, which were packed by helices ␣2 and ␣4 on either side (15).…”

“…The solution structure of human MOG1 was determined recently by conventional NMR spectroscopy and has a sandwich-like structure with nine ␤-strands and four helices (15). The ␤3 to ␤9 form the central antiparallel ␤-sheets, which were packed by helices ␣2 and ␣4 on either side (15). The Asp-25, Arg-30, Asp-34, and Glu-37 residues of MOG1 play an important role in Ran binding and GTP release in mice (16).…”

“…The Asp-25, Arg-30, Asp-34, and Glu-37 residues of MOG1 play an important role in Ran binding and GTP release in mice (16). A recent study suggested that the Asp-27, Glu-50, Asp-70, and Glu-53 residues of human MOG1 were also involved in the MOG1-Ran interaction (15). 1 To whom correspondence may be addressed: 9500 Euclid Ave., Cleveland, OH 44195.…”

Dynamic acetylation of the kinetochore-associated protein HEC1 ensures accurate microtubule–kinetochore attachment

“…Acetyltransferase TIP60 has been well-studied in ATM activation, p53 activation, PML stabilization for DNA damage response, and genomic stability control (24 -28). Recently, our study revealed the function of TIP60 in chro-mosome stability control during mitosis through acetylating Aurora B (29) and RAN GTPase (30,31). However, the precise mechanisms underlying accurate kinetochore microtubule attachment remain obscure.…”