| Institution: | 1. Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea;2. Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 24341, Republic of Korea;3. College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea;1. Biochemistry and Molecular Biology Department, Bioscience Faculty, Autonomous University of Barcelona, Spain;2. Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain;1. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA;2. Physics and Materials Science Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg;3. Department of Physics, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA;1. Department of Bacteriology, The Jikei University School of Medicine, Minato-Ku, Tokyo 105-8461, Japan;2. Jikei Center for Biofilm Science and Technology, The Jikei University School of Medicine, Minato-Ku, Tokyo 105-8461, Japan;3. Department of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto 860-0811, Japan;4. Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8503, Japan;1. Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, CONICET, Bernal, Buenos Aires, Argentina;2. Department of Biomedical Sciences, University of Padua, Padua, Italy;3. Sorbonne Université, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Paris, France |
| Abstract: | Legionella pneumophila infects alveolar macrophages and can cause life-threatening pneumonia in humans. Upon internalization into the host cell, L. pneumophila injects numerous effector proteins into the host cytoplasm as a part of its pathogenesis. LegK7 is an effector kinase of L. pneumophila that functionally mimics the eukaryotic Mst kinase and phosphorylates the host MOB1 protein to exploit the Hippo pathway. To elucidate the LegK7 activation mechanism, we determined the apo structure of LegK7 in an inactive form and performed a comparative analysis of LegK7 structures. LegK7 is a non-RD kinase that contains an activation segment that is ordered, irrespective of stimulation, through a unique β-hairpin-containing segment, and it does not require phosphorylation of the activation segment for activation. Instead, bacterial LegK7 becomes an active kinase via its heterologous molecular interaction with the host MOB1 protein. MOB1 binding triggers reorientation of the two lobes of the kinase domain, as well as a structural change in the interlobe hinge region in LegK7, consequently reshaping the LegK7 structure into an ATP binding-compatible closed conformation. Furthermore, we reveal that LegK7 is an atypical kinase that contains an N-terminal capping domain and a hydrophilic interlobe linker motif, which play key roles in the MOB1-induced activation of LegK7. |
