Shugoshin is a Mad1/Cdc20-like interactor of Mad2

Abstract

Mammalian centromeric cohesin is protected from phosphorylation‐dependent displacement in mitotic prophase by shugoshin‐1 (Sgo1), while shugoshin‐2 (Sgo2) protects cohesin from separase‐dependent cleavage in meiosis I. In higher eukaryotes, progression and faithful execution of both mitosis and meiosis are controlled by the spindle assembly checkpoint, which delays anaphase onset until chromosomes have achieved proper attachment to microtubules. According to the so‐called template model, Mad1–Mad2 complexes at unattached kinetochores instruct conformational change of soluble Mad2, thus catalysing Mad2 binding to its target Cdc20. Here, we show that human Sgo2, but not Sgo1, specifically interacts with Mad2 in a manner that strongly resembles the interactions of Mad2 with Mad1 or Cdc20. Sgo2 contains a Mad1/Cdc20‐like Mad2‐interaction motif and competes with Mad1 and Cdc20 for binding to Mad2. NMR and biochemical analyses show that shugoshin binding induces similar conformational changes in Mad2 as do Mad1 or Cdc20. Mad2 binding regulates fine‐tuning of Sgo2's sub‐centromeric localization. Mad2 binding is conserved in the only known Xenopus laevis shugoshin homologue and, compatible with a putative meiotic function, the interaction occurs in oocytes.

Checkpoint-Independent Stabilization of Kinetochore-Microtubule Attachments by Mad2 in Human Cells

“…At present, the molecular details for how any of these checkpoint proteins influence Aurora B activity remains unknown, but our evidence shows that there are at least two separate pathways. Since neither Mad2 nor CDC20 co-localize with Aurora B at centromeres, there must be molecular intermediates in this pathway (Figure 4E), and one candidate is the centromeric protein Sgo2 that has recently been shown to bind Mad2 [40]. Finally, we show that overexpression of Mad2 hyperstabilizes k-MT attachments (Figure 4E) which impairs the correction of k-MT attachment errors such as merotely.…”

Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis

“…Depletion of Sgo1 in human cells causes massive chromosome missegregation, but does not appreciably alter the centromeric localization of PP2A 18,21 . By contrast, Sgo2 is required for PP2A centromeric targeting in human cells 21 , but is largely dispensable for chromosome segregation during mitosis 30 . In fact, Sgo2 knockout mice are viable but infertile 31 , indicating that mammalian Sgo2 is specifically required for meiosis, but not for mitosis.…”

The Chromosome Axis Controls Meiotic Events through a Hierarchical Assembly of HORMA Domain Proteins

“…Other interactions in the HTP-1 and HTP-2 complexes are mostly backbone-backbone hydrogen bonds characteristic of β-sheets, providing little sequence specificity. This is reminiscent of Mad2, whose known binding peptides in Cdc20, Mad1, and Shugoshin bear only weak sequence similarity (Luo et al, 2002; Orth et al, 2011). …”