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4ynz

From Proteopedia

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Current revision

Structure of the N-terminal domain of SAD

Structural highlights

4ynz is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BRSK2_MOUSE Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion. Phosphorylates CDK16, CDC25C, MAPT/TAU, PAK1 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-504' and 'Ser-554'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in post-mitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. Plays a role in the regulation of the mitotic cell cycle progress and the onset of mitosis. Plays a role in the regulation of insulin secretion in response to elevated glucose levels, probably via phosphorylation of CDK16 and PAK1. While BRSK2 phosphorylated at Thr-175 can inhibit insulin secretion (PubMed:22798068), BRSK2 phosphorylated at Thr-261 can promote insulin secretion (PubMed:22669945). Regulates reorganization of the actin cytoskeleton. May play a role in the apoptotic response triggered by endoplasmatic reticulum (ER) stress.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an 'alphaC-out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases.

Structural insight into the mechanism of synergistic autoinhibition of SAD kinases.,Wu JX, Cheng YS, Wang J, Chen L, Ding M, Wu JW Nat Commun. 2015 Dec 2;6:8953. doi: 10.1038/ncomms9953. PMID:26626945^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kishi M, Pan YA, Crump JG, Sanes JR. Mammalian SAD kinases are required for neuronal polarization. Science. 2005 Feb 11;307(5711):929-32. PMID:15705853 doi:http://dx.doi.org/307/5711/929
↑ Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN, Sanes JR, Polleux F. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell. 2007 May 4;129(3):549-63. PMID:17482548 doi:http://dx.doi.org/10.1016/j.cell.2007.03.025
↑ Muller M, Lutter D, Puschel AW. Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity. J Cell Sci. 2010 Jan 15;123(Pt 2):286-94. doi: 10.1242/jcs.058230. Epub 2009 Dec , 21. PMID:20026642 doi:http://dx.doi.org/10.1242/jcs.058230
↑ Nie J, Sun C, Faruque O, Ye G, Li J, Liang Q, Chang Z, Yang W, Han X, Shi Y. Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-Cells. J Biol Chem. 2012 Jul 27;287(31):26435-44. doi: 10.1074/jbc.M112.378372. Epub, 2012 Jun 5. PMID:22669945 doi:10.1074/jbc.M112.378372
↑ Chen XY, Gu XT, Saiyin H, Wan B, Zhang YJ, Li J, Wang YL, Gao R, Wang YF, Dong WP, Najjar SM, Zhang CY, Ding HF, Liu JO, Yu L. Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic beta-cells. J Biol Chem. 2012 Aug 31;287(36):30368-75. doi: 10.1074/jbc.M112.375618. Epub, 2012 Jul 13. PMID:22798068 doi:10.1074/jbc.M112.375618
↑ Wu JX, Cheng YS, Wang J, Chen L, Ding M, Wu JW. Structural insight into the mechanism of synergistic autoinhibition of SAD kinases. Nat Commun. 2015 Dec 2;6:8953. doi: 10.1038/ncomms9953. PMID:26626945 doi:http://dx.doi.org/10.1038/ncomms9953

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ynz"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4ynz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YNZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YNZ FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ynz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynz OCA], [https://pdbe.org/4ynz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ynz RCSB], [https://www.ebi.ac.uk/pdbsum/4ynz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynz ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ynz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynz OCA], [https://pdbe.org/4ynz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ynz RCSB], [https://www.ebi.ac.uk/pdbsum/4ynz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynz ProSAT]</span></td></tr>
 </table>
 == Function ==

4ynz

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Current revision

Structure of the N-terminal domain of SAD

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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