Uncovering the Human Methyltransferasome

Tanya C. Petrossian,Steven G. Clarke

doi:10.1074/mcp.m110.000976

Abstract

We present a comprehensive analysis of the human methyltransferasome. Primary sequences, predicted secondary structures, and solved crystal structures of known methyltransferases were analyzed by hidden Markov models, Fisher-based statistical matrices, and fold recognition prediction-based threading algorithms to create a model, or profile, of each methyltransferase superfamily. These profiles were used to scan the human proteome database and detect novel methyltransferases. 208 proteins in the human genome are now identified as known or putative methyltransferases, including 38 proteins that were not annotated previously. To date, 30% of these proteins have been linked to disease states. Possible substrates of methylation for all of the SET domain and SPOUT methyltransferases as well as 100 of the 131 seven-β-strand methyltransferases were surmised from sequence similarity clusters based on alignments of the substrate-specific domains.

Highlights

A significant percentage of proteins across all organisms are enzymes that catalyze the transfer of a methyl group from the cofactor S-adenosylmethionine to a substrate [1,2,3,4,5]
This profile was used against the non-redundant human proteome database using the programs HHpred with the PsiPred parameter and FHMMER
Human Methyltransferasome—We wanted to identify all of the S-adenosylmethionine-dependent methyltransferases that are encoded in the human genome

Summary

Identification of Novel Human Methyltransferases

Methodology used for each superfamily depended on the abundance of information known on the specific family. Seven-␤-strand Methyltransferases—We previously defined a “yeast reference set” profile based on the primary sequence and secondary structural characteristics of the amino acids within the signature motifs of these enzymes [5] This profile was used against the non-redundant human proteome database using the programs HHpred with the PsiPred parameter and FHMMER (supplemental Table I). To confirm that the methyltransferase domain was adequately represented by the inherently non-redundant yeast seven-␤strand methyltransferasome, the “crystal reference set” profile [5] was used as a secondary input with these programs This profile includes methyltransferases from all non-yeast organisms with solved structures to ensure proper domain/motif identification; these enzymes are diverse in both function and organismal source [5]. SPOUT methyltransferase groups were clustered with yeast SPOUT methyltransferases [6] and with all members within the SPOUT UniProt subfamilies [40]

RESULTS AND DISCUSSION

Substrate specificity

TABLE III Classification of human SET domain methyltransferases