Kinase Family MLKL
Kinase Classification: Group TKL: Family MLKL
MLKL is a pseudokinase involved in necroptosis, a form of programmed cell death.
Evolution
MLKL is found throughout deuterostomes, including sea urchin, several invertebrate chordates, and most vertebrates. It has been lost from several clades of animals, including marsupials and carnivores. It has also been found in several poxviruses.
Domain Structure
Eukaryotic MLKL consist of an N-terminal 4HB (4 helix bundle) domain [1] followed by an pseudokinase domain. Though named MLKL for Mixed Lineage Kinase-Like, the sequence is only marginally if at all closer to MLKs than other TKLs, and may even be derived from RIPKs, their upstream kinase. Viral homologs encode only the kinase domain.
Functions
Mammalian MLKL is activated by phosphorylation on its activation loop by RIPK3, which in turn is activated by RIPK1 and several death-promoting stimuli, such as TNF. MLKL is then thought to insert the 4HB domain to the membrane as an oligomer, destroying cellular integrity and leading to programmed necrotic death, or necroptosis [2].
Primary Data
See the enclosed multiple sequence alignment of selected MLKL members.
References
- Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, and Alexander WS. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013 Sep 19;39(3):443-53. DOI:10.1016/j.immuni.2013.06.018 |
- Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RC, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, and Silke J. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7. DOI:10.1073/pnas.1408987111 |
