Protein metamorphosis: the two-state behavior of Mad2.
A given protein generally has only one native tertiary fold, which is the conformation with the lowest Gibbs free energy. Mad2, a protein involved in the spindle checkpoint, however, has two natively folded states with similar Gibbs free energies. Through binding to its target Cdc20, Mad2 inhibits the multisubunit ubiquitin ligase, the anaphase-promoting complex or cyclosome (APC/C), and delays the onset of anaphase until all sister chromatids achieve bipolar attachment to the mitotic spindle. Without ligand binding or covalent modifications, Mad2 adopts two topologically and functionally distinct native folds in equilibrium under physiological conditions. The transition between the two Mad2 states is regulated by multiple mechanisms and is central to the activation and inactivation of the spindle checkpoint. This review summarizes recent structural and biochemical studies on the two-state behavior of Mad2 and discusses the generality and implications of structural malleability of proteins.
Luo
Xuelian
X
Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. xuelian.luo@utsouthwestern.edu
Yu
Hongtao
H
D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D004531:Eggs; D006801:Humans; D064246:Mad2 Proteins; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D014981:Xenopus
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D018620:PrPSc Proteins; D011328:Prions; D011994:Recombinant Proteins; D012097:Repressor Proteins