6LK5

MLKL mutant - T357ES358D

Summary for 6LK5

• Entry DOI: 10.2210/pdb6lk5/pdb
• Descriptor: Mixed lineage kinase domain-like protein (2 entities in total)
• Functional Keywords: protein phosphorylation, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 54621.08

Authors

Wang, H.Y.,Li, S.,Zhang, Y. (deposition date: 2019-12-18, release date: 2020-12-23, Last modification date: 2023-11-22)

Primary citation

Zhang, Y.,Liu, J.,Yu, D.,Zhu, X.,Liu, X.,Liao, J.,Li, S.,Wang, H.
The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling.
Cell Death Dis, 12:638-638, 2021

PubMed Abstract: MLKL phosphorylation by RIP3 is the commitment step of necroptosis execution, which could induce MLKL activation featured as MLKL monomer-oligomer transition. Here, we reported that the dimerization of the MLKL kinase-like domain was the direct consequence of RIP3 triggered MLKL-phosphorylation. Two inter-dimer interfaces were found in the crystal structure of human MLKL. Mutations destroying both interfaces could prevent RIP3-induced MLKL oligomerization and necroptosis efficiently. Moreover, we confirmed MLKL self-assembly by the internal coiled-coil region is necessary for MLKL oligomerization and function. The mutations disrupting coiled-coil self-assembly repressed necroptosis, but it did not prevent RIP3-induced dimerization of the MLKL kinase-like domain. So that, MLKL activation is a sequential process, which begins with kinase-like domain dimerization, and followed by internal coiled-coil region self-assembly to form a proper MLKL oligomer. Besides human MLKL, structural and functional analysis showed the kinase-like domain dimerization was conserved among mammalian species, suggesting it is a general step of the RIP3-induced MLKL activation process.

PubMed: 34158471
DOI: 10.1038/s41419-021-03859-6

Experimental method

X-RAY DIFFRACTION (2.5 Å)