5jja
From Proteopedia
Crystal structure of a PP2A B56gamma/BubR1 complex
Structural highlights
Disease[BUB1B_HUMAN] Mosaic variegated aneuploidy syndrome. Defects in BUB1B are associated with tumor formation. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. MVA1 is caused by biallelic mutations in the BUB1B gene. Function[2A5G_HUMAN] The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment. The PP2A-PPP2R5C holoenzyme may specifically dephosphorylate and activate TP53 and play a role in DNA damage-induced inhibition of cell proliferation. PP2A-PPP2R5C may also regulate the ERK signaling pathway through ERK dephosphorylation.[1] [2] [BUB1B_HUMAN] Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression.[3] [4] [5] [6] [7] [8] Publication Abstract from PubMedProtein phosphatase 2A (PP2A) accounts for the majority of total Ser/Thr phosphatase activities in most cell types and regulates many biological processes. PP2A holoenzymes contain a scaffold A subunit, a catalytic C subunit, and one of the regulatory/targeting B subunits. How the B subunit controls PP2A localization and substrate specificity, which is a crucial aspect of PP2A regulation, remains poorly understood. The kinetochore is a critical site for PP2A functioning, where PP2A orchestrates chromosome segregation through its interactions with BubR1. The PP2A-BubR1 interaction plays important roles in both spindle checkpoint silencing and stable microtubule-kinetochore attachment. Here we present the crystal structure of a PP2A B56-BubR1 complex, which demonstrates that a conserved BubR1 LxxIxE motif binds to the concave side of the B56 pseudo-HEAT repeats. The BubR1 motif binds to a groove formed between B56 HEAT repeats 3 and 4, which is quite distant from the B56 binding surface for PP2A catalytic C subunit and thus is unlikely to affect PP2A activity. In addition, the BubR1 binding site on B56 is far from the B56 binding site of shugoshin, another kinetochore PP2A-binding protein, and thus BubR1 and shugoshin can potentially interact with PP2A-B56 simultaneously. Our structural and biochemical analysis indicates that other proteins with the LxxIxE motif may also bind to the same PP2A B56 surface. Thus, our structure of the PP2A B56-BubR1 complex provides important insights into how the B56 subunit directs the recruitment of PP2A to specific targets. Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization.,Wang J, Wang Z, Yu T, Yang H, Virshup DM, Kops GJ, Lee SH, Zhou W, Li X, Xu W, Rao Z Protein Cell. 2016 Jul;7(7):516-26. doi: 10.1007/s13238-016-0283-4. Epub 2016 Jun, 28. PMID:27350047[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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