A New Methylation Site on P53 Found

Structure published online the research results of Chen Yong's research group at the Center for Excellence in Molecular Cell Science (Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences "Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases".

This work revealed that MLL family proteins can catalyze the methylation of P53 through structural biology studies of the MLL2-RBBP5-ASH2L methyltransferase complex, and identified a new lysine methylation site on P53.

MLL family proteins (MLL1/2/3/4, SET1A/B) play an important role in gene expression regulation, cell proliferation, differentiation and other life activities, and are closely related to the occurrence and development of leukemia and other diseases.

Previous studies have focused on the activity of catalyzing the methylation of lysine (H3K4) at position 4 of histone H3, and it is believed that diseases caused by abnormal function of MLL family proteins are closely related to abnormal H3K4 methylation levels..

In recent years, it has been discovered that many histone lysine methyltransferases have non-histone substrates.

For example, SET1A, one of the members of the MLL family of proteins, was shown in 2018 to catalyze the methylation of YAP protein K342, a key effector molecule of the Hippo pathway, thereby increasing the residence time of YAP in the nucleus and promoting YAP transcription and tumorigenesis.

Are there other non-histone substrates for MLL family proteins? Is the life activity process they participate in is far more complicated than we know?

Chen Yong's research group has long been committed to the structure and function research of MLL family protein complexes.

In this work, the researchers solved the crystal structure of the MLL2-RBBP5-ASH2L core complex, in which an asymmetric unit is composed of two M2RA complexes due to crystal packing, and one of the MLL2 SET domain N-terminal loop (NFL) can be inserted into the catalytic pocket of the other MLL2.

Interestingly, the conformation of this NFL is very consistent with the conformation of H3 in the M3RA-H3 complex, but the sequence is very different, indicating that MLL family proteins have the ability to recognize and bind to sequences other than H3.

According to the sequence characteristics of MLL2 NFL, the researchers used the ScanProsite database and found that there is a sequence in P53 that is very similar to MLL2 NFL.

Subsequently, through a series of biochemical experiments combined with mass spectrometry technology, they revealed that the MLL family protein complex can catalyze the methylation of P53 K305 in vitro. This is a brand new P53 methylation site.

The methylation sites of P53 reported in the past are mostly concentrated at the C-terminus of P53, and the methylation sites found in this article are located between the tetramerization domain of P53 and the DNA binding domain. It may affect the transcriptional activity of P53, and the specific function needs to be further explored later.

Lysine methylation modification of P53 is a new P53 post-translational modification discovered in recent years. Abnormal P53 methylation modification often affects the transcriptional activity of P53 and causes P53-related diseases.

The discovery of this site and the identification of the key enzyme responsible for the methylation modification of this site provide new ideas and research perspectives for people to further explore the physiological significance of P53 methylation and to understand the functional regulation of P53 in cells.

At the same time, the research ideas of this research content are also worthy of further promotion in other research directions, that is, the use of known structural biological information to predict unknown biological phenomena, and continuously enrich our relevant understanding of the dynamic regulation process of proteins in cells.

Randi Warren from Creative Biostructure.