The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
The Mad2 spindle checkpoint protein has two distinct natively folded states
Abstract
The spindle checkpoint delays chromosome segregation in response to misaligned sister chromatids during mitosis, thus ensuring the fidelity of chromosome inheritance. Through binding to Cdc20, the Mad2 spindle checkpoint protein inhibits the target of this checkpoint, the ubiquitin protein ligase APC/C(Cdc20). We now show that without cofactor binding or covalent modification Mad2 adopts two distinct folded conformations at equilibrium (termed N1-Mad2 and N2-Mad2). The structure of N2-Mad2 has been determined by NMR spectroscopy. N2-Mad2 is much more potent in APC/C inhibition. Overexpression of a Mad2 mutant that specifically sequesters N2-Mad2 partially blocks checkpoint signaling in living cells. The two Mad2 conformers interconvert slowly in vitro, but interconversion is accelerated by a fragment of Mad1, an upstream regulator of Mad2. Our results suggest that the unusual two-state behavior of Mad2 is critical for spindle checkpoint signaling.
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“MAD2 has two topologically distinct monomeric structures that are in equilibrium under physiological conditions27.”
From Predicting multiple conformations via sequence clustering and AlphaFold2 (2024) · cites this paper as [27]
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The spindle-assembly checkpoint in space and time
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The Spindle Assembly Checkpoint
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Metadata
- Authors
- Luo, X., Tang, Z., Xia, G., Wassmann, K., Matsumoto, T., Rizo, J., & Yu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- Kyoto University (JP)
- Corresponding author
- Rizo, Josep
- Yu, Hongtao
- Venue
- Nature Structural & Molecular Biology
- Published
- 2004-03-14
- Volume
- 11
- Issue
- 4
- Pages
- 338-345
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2112512547
- Cited by
- 297
- References
- 42
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 16 · 2022: 14 · 2021: 11 · 2020: 12 · 2019: 6 · 2018: 18 · 2017: 15 · 2016: 16 · 2015: 17 · 2014: 17 · 2013: 15 · 2012: 9
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Mad2, spindle assembly checkpoint, conformational equilibrium, protein folding, CDC20, Mad1, mitosis, chromosome segregation fidelity, NMR structure
- MeSH terms
- Calcium-Binding Proteins, Cloning, Molecular, HeLa Cells, Humans, Spindle Apparatus, Magnetic Resonance Spectroscopy, Protein Conformation, Recombinant Proteins, Repressor Proteins, Transfection, Restriction Mapping, Cyclins, Protein Folding, Cell Cycle Proteins, Cdc20 Proteins, Mad2 Proteins
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