Structural highlights
Function
[BRSK1_MOUSE] Serine/threonine-protein kinase that plays a key role in polarization of neurons and centrosome duplication. Phosphorylates CDC25B, CDC25C, MAPT/TAU, RIMS1, TUBG1, TUBG2 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. In neurons, localizes to synaptic vesicles and plays a role in neurotransmitter release, possibly by phosphorylating RIMS1. Also acts as a positive regulator of centrosome duplication by mediating phosphorylation of gamma-tubulin (TUBG1 and TUBG2) at 'Ser-131', leading to translocation of gamma-tubulin and its associated proteins to the centrosome. Involved in the UV-induced DNA damage checkpoint response, probably by inhibiting CDK1 activity through phosphorylation and activation of WEE1, and inhibition of CDC25B and CDC25C.[1] [2] [3] [4]
Publication Abstract from PubMed
The SAD (synapses of amphids defective) kinases, including SAD-A and SAD-B, play important roles in the regulation of neuronal development, cell cycle, and energy metabolism. Our recent study of mouse SAD-A identified a unique autoinhibitory sequence (AIS), which binds at the junction of the kinase domain (KD) and the ubiquitin-associated (UBA) domain and exerts autoregulation in cooperation with UBA. Here, we report the crystal structure of the mouse SAD-B C-terminal fragment including the AIS and the kinase-associated domain 1 (KA1) at 2.8 A resolution. The KA1 domain is structurally conserved, while the isolated AIS sequence is highly flexible and solvent-accessible. Our biochemical studies indicated that the SAD-B AIS exerts the same autoinhibitory role as that in SAD-A. We believe that the flexible isolated AIS sequence is readily available for interaction with KD-UBA and thus inhibits SAD-B activity.
Structure and inhibition analysis of the mouse SAD-B C-terminal fragment.,Ma H, Wu JX, Wang J, Wang ZX, Wu JW Biosci Biotechnol Biochem. 2016 Jun 2:1-8. PMID:27251228[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Alvarado-Kristensson M, Rodriguez MJ, Silio V, Valpuesta JM, Carrera AC. SADB phosphorylation of gamma-tubulin regulates centrosome duplication. Nat Cell Biol. 2009 Sep;11(9):1081-92. Epub 2009 Aug 2. PMID:19648910 doi:http://dx.doi.org/ncb1921
- ↑ 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
- ↑ Ma H, Wu JX, Wang J, Wang ZX, Wu JW. Structure and inhibition analysis of the mouse SAD-B C-terminal fragment. Biosci Biotechnol Biochem. 2016 Jun 2:1-8. PMID:27251228 doi:http://dx.doi.org/10.1080/09168451.2016.1191331
