title: Structure and inhibition analysis of the mouse SAD-B C-terminal fragment.
abstract: 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 Å 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.
authors.affiliation: a MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences , School of Life Sciences, Tsinghua University , Beijing , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: a MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences , School of Life Sciences, Tsinghua University , Beijing , China.
authors.forename: Jing-Xiang
authors.initials: JX
authors.lastname: Wu
authors.affiliation: a MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences , School of Life Sciences, Tsinghua University , Beijing , China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: a MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences , School of Life Sciences, Tsinghua University , Beijing , China.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Wang
authors.affiliation: a MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences , School of Life Sciences, Tsinghua University , Beijing , China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; C496826:Brsk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: autoinhibitory sequence (AIS); crystal structure; kinase associated domain 1 (KA1); synapses of amphids defective (SAD)