2VFX

Structure of the Symmetric Mad2 Dimer

Summary for 2VFX

• Entry DOI: 10.2210/pdb2vfx/pdb
• Related: 1DUJ 1GO4 1KLQ 1S2H 2V64
• Descriptor: MITOTIC SPINDLE ASSEMBLY CHECKPOINT PROTEIN MAD2A, MAGNESIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: mad2, mad1, cdc2, nucleus, mitosis, anaphase, cell cycle, cell division, spindle checkpoint, anaphase-promoting complex
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 12
• Total formula weight: 288684.83

Authors

Yang, M.,Li, B.,Liu, C.-J.,Tomchick, D.R.,Machius, M.,Rizo, J.,Yu, H.,Luo, X. (deposition date: 2007-11-05, release date: 2008-03-18, Last modification date: 2023-12-13)

Primary citation

Yang, M.,Li, B.,Liu, C.-J.,Tomchick, D.R.,Machius, M.,Rizo, J.,Yu, H.,Luo, X.
Insights Into MAD2 Regulation in the Spindle Checkpoint Revealed by the Crystal Structure of the Symmetric MAD2 Dimer.
Plos Biol., 6:E50-, 2008

PubMed Abstract: In response to misaligned sister chromatids during mitosis, the spindle checkpoint protein Mad2 inhibits the anaphase-promoting complex or cyclosome (APC/C) through binding to its mitotic activator Cdc20, thus delaying anaphase onset. Mad1, an upstream regulator of Mad2, forms a tight core complex with Mad2 and facilitates Mad2 binding to Cdc20. In the absence of its binding proteins, free Mad2 has two natively folded conformers, termed N1-Mad2/open-Mad2 (O-Mad2) and N2-Mad2/closed Mad2 (C-Mad2), with C-Mad2 being more active in APC/C(Cdc20) inhibition. Here, we show that whereas O-Mad2 is monomeric, C-Mad2 forms either symmetric C-Mad2-C-Mad2 (C-C) or asymmetric O-Mad2-C-Mad2 (O-C) dimers. We also report the crystal structure of the symmetric C-C Mad2 dimer, revealing the basis for the ability of unliganded C-Mad2, but not O-Mad2 or liganded C-Mad2, to form symmetric dimers. A Mad2 mutant that predominantly forms the C-C dimer is functional in vitro and in living cells. Finally, the Mad1-Mad2 core complex facilitates the conversion of O-Mad2 to C-Mad2 in vitro. Collectively, our results establish the existence of a symmetric Mad2 dimer and provide insights into Mad1-assisted conformational activation of Mad2 in the spindle checkpoint.

PubMed: 18318601
DOI: 10.1371/JOURNAL.PBIO.0060050

Experimental method

X-RAY DIFFRACTION (1.95 Å)