Lysine Methylation-Dependent Proteolysis by the Malignant Brain Tumor (MBT) Domain Proteins

Abstract

Lysine methylation is a major post-translational protein modification that occurs in both histones and non-histone proteins. Emerging studies show that the methylated lysine residues in non-histone proteins provide a proteolytic signal for ubiquitin-dependent proteolysis. The SET7 (SETD7) methyltransferase specifically transfers a methyl group from S-Adenosyl methionine to a specific lysine residue located in a methylation degron motif of a protein substrate to mark the methylated protein for ubiquitin-dependent proteolysis. LSD1 (Kdm1a) serves as a demethylase to dynamically remove the methyl group from the modified protein. The methylated lysine residue is specifically recognized by L3MBTL3, a methyl-lysine reader that contains the malignant brain tumor domain, to target the methylated proteins for proteolysis by the CRL4^DCAF5 ubiquitin ligase complex. The methylated lysine residues are also recognized by PHF20L1 to protect the methylated proteins from proteolysis. The lysine methylation-mediated proteolysis regulates embryonic development, maintains pluripotency and self-renewal of embryonic stem cells and other stem cells such as neural stem cells and hematopoietic stem cells, and controls other biological processes. Dysregulation of the lysine methylation-dependent proteolysis is associated with various diseases, including cancers. Characterization of lysine methylation should reveal novel insights into how development and related diseases are regulated.

Keywords: CRL4; DCAF5; L3MBTL3; LSD1/Kdm1a; SET7/SETD7; demethylation; lysine methylation; ubiquitin E3 ligase.

Figure 1

(A) The H3K4-like methylation motifs in methylated proteins. K* denotes the methylated lysine residues. (B) A model for the K42- and K117-methylation-dependent degradation of human SOX2 by L3MBTL3 and the CRL4-DCAF5 ubiquitin ligase complex. Other lysine methylated substrates in A are similarly regulated.

Figure 2

The domains in Drosophila (Dm) L3mbt, SCM, and SFMBT, and human (Hs) L3MBTL1, L3MBTL3, L3MBTL4, L3MBTL2, MBTD1, SCMH1, SCML2, SFMBT1, SFMBT2, and PHF20L1. MBT: the malignant brain tumor motif, zf-HC/zf-c2: zinc finger motif, RBR: RNA binding region, SLED: Scm-like embedded domain, SPM/SAM: SCM, PH, and MBT homology/Sterile α motif domain.