mitotic spindle assembly checkpoint protein MAD2A; HsMAD2; mitotic arrest deficient 2-like protein 1; MAD2-like protein 1 (MAD2L1, MAD2)

Function

• component of the spindle-assembly checkpoint
• required for execution of the which monitors the process of kinetochore-spindle attachment & inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate
• phosphorylated on multiple Ser
  • phosphorylation varies during the cell cycle & is highest during mitosis
  • phosphorylation abolishes interaction with MAD1L1 & reduces interaction with CDC20
• monomer & homodimer
• heterotetramer with MAD1L1
• formation of a heterotetrameric core complex containing 2 molecules each of MAD1L1 & of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer
• interacts with CDC20, MAD2L1BP & with ADAM17/TACE
• dimeric MAD2L1 in the closed conformation interacts with CDC20
• monomeric MAD2L1 in the open conformation does not interact with CDC20
• CDC20 competes with MAD1L1 for MAD2L1 binding
• interacts with TPR
• binds to UBD during mitosis

Structure

• the protein has two highly different native conformations,
  • an inactive open conformation that cannot bind CDC20 & that predominates in cytosolic monomers
  • an active closed conformation
• the protein in the closed conformation preferentially dimerizes with another molecule in the open conformation, but can also form a dimer with a molecule in the closed conformation
• formation of a heterotetrameric core complex containing 2 molecules of MAD1L1 & of MAD2L1 in the closed conformation promotes binding of another molecule of MAD2L1 in the open conformation & the conversion of the open to the closed form, & thereby promotes interaction with CDC20
• belongs to the MAD2 family
• contains 1 HORMA domain

Compartment

• nucleus, kinetochore, cytoplasm
• recruited by MAD1L1 to unattached kinetochores (probable)
• recruited to the nuclear pore complex by TPR during interphase
• recruited to kinetochores in late prometaphase after BUB1, CENPF, BUB1B & CENPE
• kinetochore association requires the presence of NEK2
• kinetochore association is repressed by UBD

More general terms

• phosphoprotein
• nuclear protein

Component of

• spindle-assembly checkpoint

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4085
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4085
• OMIM: https://mirror.omim.org/entry/601467
• UniProt: http://www.uniprot.org/uniprot/Q13257.html