4ZRI

Crystal structure of Merlin-FERM and Lats2

Summary for 4ZRI

• Entry DOI: 10.2210/pdb4zri/pdb
• Related: 4ZRJ 4ZRK
• Descriptor: Merlin, Serine/threonine-protein kinase LATS2 (3 entities in total)
• Functional Keywords: merlin, ferm, lats2, signaling protein-transferase complex, signaling protein/transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Cell projection, filopodium membrane; Peripheral membrane protein; Cytoplasmic side. Isoform 7: Cytoplasm, perinuclear region. Isoform 9: Cytoplasm, perinuclear region. Isoform 10: Nucleus: P35240; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: Q9NRM7
• Total number of polymer chains: 4
• Total formula weight: 83089.76

Authors

Li, F.,Zhou, H.,Long, J.,Shen, Y. (deposition date: 2015-05-12, release date: 2015-06-17, Last modification date: 2024-11-13)

Primary citation

Li, Y.,Zhou, H.,Li, F.,Chan, S.W.,Lin, Z.,Wei, Z.,Yang, Z.,Guo, F.,Lim, C.J.,Xing, W.,Shen, Y.,Hong, W.,Long, J.,Zhang, M.
Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
Cell Res., 25:801-817, 2015

PubMed Abstract: The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4(DCAF1). Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

PubMed: 26045165
DOI: 10.1038/cr.2015.69

Experimental method

X-RAY DIFFRACTION (2.7 Å)