| Structural highlights
Disease
[KIF4A_HUMAN] The disease may be caused by mutations affecting the gene represented in this entry.
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] [KIF4A_HUMAN] Motor protein that translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis. May play a role in mitotic chromosomal positioning and bipolar spindle stabilization.[3] [4]
Publication Abstract from PubMed
The recruitment of substrates by the ser/thr protein phosphatase 2A (PP2A) is poorly understood, limiting our understanding of PP2A-regulated signaling. Recently, the first PP2A:B56 consensus binding motif, LxxIxE, was identified. However, most validated LxxIxE motifs bind PP2A:B56 with micromolar affinities, suggesting that additional motifs exist to enhance PP2A:B56 binding. Here, we report the requirement of a positively charged motif in a subset of PP2A:B56 interactors, including KIF4A, to facilitate B56 binding via dynamic, electrostatic interactions. Using molecular and cellular experiments, we show that a conserved, negatively charged groove on B56 mediates dynamic binding. We also discovered that this positively charged motif, in addition to facilitating KIF4A dephosphorylation, is essential for condensin I binding, a function distinct and exclusive from PP2A-B56 binding. Together, these results reveal how dynamic, charge-charge interactions fine-tune the interactions mediated by specific motifs, providing a new framework for understanding how PP2A regulation drives cellular signaling.
A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment.,Wang X, Garvanska DH, Nasa I, Ueki Y, Zhang G, Kettenbach AN, Peti W, Nilsson J, Page R Elife. 2020 Mar 20;9. pii: 55966. doi: 10.7554/eLife.55966. PMID:32195664[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Letourneux C, Rocher G, Porteu F. B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J. 2006 Feb 22;25(4):727-38. Epub 2006 Feb 2. PMID:16456541 doi:http://dx.doi.org/10.1038/sj.emboj.7600980
- ↑ Li HH, Cai X, Shouse GP, Piluso LG, Liu X. A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J. 2007 Jan 24;26(2):402-11. PMID:17245430 doi:http://dx.doi.org/10.1038/sj.emboj.7601519
- ↑ Kurasawa Y, Earnshaw WC, Mochizuki Y, Dohmae N, Todokoro K. Essential roles of KIF4 and its binding partner PRC1 in organized central spindle midzone formation. EMBO J. 2004 Aug 18;23(16):3237-48. Epub 2004 Aug 5. PMID:15297875 doi:10.1038/sj.emboj.7600347
- ↑ Zhu C, Jiang W. Cell cycle-dependent translocation of PRC1 on the spindle by Kif4 is essential for midzone formation and cytokinesis. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):343-8. Epub 2004 Dec 29. PMID:15625105 doi:0408438102
- ↑ Wang X, Garvanska DH, Nasa I, Ueki Y, Zhang G, Kettenbach AN, Peti W, Nilsson J, Page R. A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment. Elife. 2020 Mar 20;9. pii: 55966. doi: 10.7554/eLife.55966. PMID:32195664 doi:http://dx.doi.org/10.7554/eLife.55966
|
