The vertebrate mitotic checkpoint protein BUBR1 is an unusual pseudokinase.
Chromosomal stability is safeguarded by a mitotic checkpoint, of which BUB1 and Mad3/BUBR1 are core components. These paralogs have similar, but not identical, domain organization. We show that Mad3/BUBR1 and BUB1 paralogous pairs arose by nine independent gene duplications throughout evolution, followed by parallel subfunctionalization in which preservation of the ancestral, amino-terminal KEN box or kinase domain was mutually exclusive. In one exception, vertebrate BUBR1-defined by the KEN box-preserved the kinase domain but allowed nonconserved degeneration of catalytic motifs. Although BUBR1 evolved to a typical pseudokinase in some vertebrates, it retained the catalytic triad in humans. However, we show that putative catalysis by human BUBR1 is dispensable for error-free chromosome segregation. Instead, residues that interact with ATP in conventional kinases are essential for conformational stability in BUBR1. We propose that parallel evolution of BUBR1 orthologs rendered its kinase function dispensable in vertebrates, producing an unusual, triad-containing pseudokinase.
Molecular Cancer Research and Cancer Genomics Centre, Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Saskia J E
SJ
Suijkerbuijk
Teunis J P
TJ
van Dam
G Elif
GE
Karagöz
Eleonore
E
von Castelmur
Nina C
NC
Hubner
Afonso M S
AM
Duarte
Mathijs
M
Vleugel
Anastassis
A
Perrakis
Stefan G D
SG
Rüdiger
Berend
B
Snel
Geert J P L
GJ
Kops
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D020090:Chromosome Segregation; D020440:Gene Duplication; D006801:Humans; D008116:Lizards; D059566:M Phase Cell Cycle Checkpoints; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D029961:Zebrafish Proteins / Q000235:genetics
D029961:Zebrafish Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases